Pediatric Nephrology

, Volume 22, Issue 12, pp 2011–2022 | Cite as

Mechanisms of progression of chronic kidney disease

  • Agnes B. FogoEmail author
Open Access
Educational Feature


Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. We will review possible mechanisms of progressive renal damage, including systemic and glomerular hypertension, various cytokines and growth factors, with special emphasis on the renin–angiotensin–aldosterone system (RAAS), podocyte loss, dyslipidemia and proteinuria. We will also discuss possible specific mechanisms of tubulointerstitial fibrosis that are not dependent on glomerulosclerosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number.


Angiotensin Angiotensin I converting enzyme inhibitors (ACEI) Angiotensin receptors Angiotensin receptor blockers Transforming growth factor (TGF)-beta Glomerulosclerosis Interstitial fibrosis Podocytes Low birth weight 


Chronic kidney disease (CKD) occurs in all age groups, with an incidence in children between 1.5 per million and 3.0 per million. Renal developmental abnormalities (congenital abnormalities of the kidney and urinary tract, CAKUT) are the most common causes of CKD in children. Other diseases commonly underlying CKD in children include focal segmental glomerulosclerosis (FSGS), hemolytic uremic syndrome (HUS), immune complex diseases, and hereditary nephropathies, such as Alport’s disease [1]. The incidence of diabetes, especially type 2, is increasing in children. Although CKD secondary to diabetes usually does not develop until adulthood, early structural lesions of diabetic nephropathy start in childhood [2].

CKD shares a common appearance of glomerulosclerosis, vascular sclerosis and tubulointerstitial fibrosis, suggesting a common final pathway of progressive injury [3]. Adaptive changes in nephrons after initial injury are postulated ultimately to be maladaptive, eventually causing scarring and further nephron loss, thus perpetuating a vicious cycle that results in the end-stage kidney. We will review possible mechanisms of progressive renal damage, which include, but are not limited to, hemodynamic factors, the renin–angiotensin–aldosterone system (RAAS), various cytokines and growth factors, podocyte loss, dyslipidemia, proteinuria, specific mechanisms of tubulointerstitial fibrosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number.

Systemic and glomerular hypertension

Systemic hypertension often accompanies renal disease and may both result from, and contribute to, CKD. Progression of CKD is accelerated by hypertension, and control of blood pressure is key in the treatment of CKD. In addition, the glomerulus has a unique structure, with both an afferent and an efferent arteriole, which permits modulation of glomerular perfusion and pressure without corresponding systemic blood pressure change.

The remnant kidney model has been extensively studied to investigate CKD [4]. In this model, one kidney and infarction/removal of two-thirds of the remaining kidney (i.e. five-sixths nephrectomy) results in progressive hyperperfusion, hyperfiltration, hypertrophy and FSGS [4, 5, 6]. Additional models with initial podocyte injury, namely the puromycin aminonucleoside and adriamycin models of renal disease, show initial proteinuria and podocyte damage similar to human minimal-change disease, followed by progressive FSGS [7].

Direct micropuncture studies have demonstrated that single nephron function was increased after renal ablation, and led to the hypothesis that hyperfiltration caused sclerosis, setting in motion a vicious cycle of hyperfiltration and glomerulosclerosis [3, 8]. Maneuvers that decreased hyperfiltration, such as low-protein diet, angiotensin I converting enzyme inhibitors (ACEIs), lipid-lowering agents, or heparin, were, indeed, effective in ameliorating glomerular sclerosis. However, in some studies, glomerular sclerosis was decreased without altering glomerular hyperfiltration [9], and glomerular sclerosis occurred in some settings even in the absence of intervening hyperperfusion [10].

Thus, focus was shifted to glomerular hypertension as a key mediator of progressive sclerosis. Maneuvers that increase glomerular capillary pressure, such as therapy with erythropoietin, glucocorticoids, or high-protein diet, accelerated glomerulosclerosis, while decreasing glomerular pressure ameliorated sclerosis. These beneficial effects were particularly apparent in the comparison of agents such as ACEIs that preferentially decrease glomerular pressure even more than systemic BP to non-specific antihypertensive agents [11].

Renin–angiotensin–aldosterone system

The RAAS has been the focus of investigation of progression in CKD because of the efficacy of inhibition of its components in CKD. ACEIs decrease glomerular capillary pressure by preferential dilation of the efferent arteriole [1], likely mediated by both inhibition of angiotensin II (AngII) and especially by the effect of ACEIs in augmenting bradykinin, which is degraded by angiotensin I converting enzyme (ACE) [12]. Indeed, angiotensin type 1 receptor blockers (ARBs), which do not have this activity to increase bradykinin, do not preferentially dilate the efferent arteriole or decrease glomerular pressures to the extent of that seen with ACEIs in most experimental studies. However, both ACEIs and ARBs have shown superior efficacy in slowing progressive CKD in experimental models and in human CKD [13, 14, 15, 16].

ARBs leave the angiotensin type 2 (AT2) receptor active, and may in theory even lead to augmented AT2 effects by allowing unbound AngII to bind to this receptor. The AT2 receptor counteracts some of the classic AT1 receptor actions and thus is mildly vasodilating and mediates growth inhibition and apoptosis [17, 18, 19, 20]. Apoptosis often is associated with decreased injury, as injured cells are quickly removed without activation of profibrotic cytokines and chemokines. Absence of AT2 receptor actions, either by pharmacological inhibition or by genetic absence, indeed resulted in diminished apoptosis after injury, associated with increased fibrosis [21, 22].

Combined ACEI and AT1 receptor antagonist treatment could have a theoretic advantage, allowing further blockade of AngII actions while maintaining preferential local availability of the AT2 receptor [23]. In an experimental model, combined ACEI and ARB therapy did not result in added benefit on glomerulosclerosis when compared with single-drug therapy with similar blood pressure control [24, 25]. However, addition of AT2 receptor inhibition to ARB treatment prevented the beneficial effects of ARBs [26]. A beneficial effect of the AT2 receptor in renal injury was also demonstrated in transgenic mice overexpressing the AT2 receptor. These mice developed less severe injury than did the wild type after subtotal nephrectomy [27]. Results from small clinical studies of human CKD suggest that the combination of ARBs and ACEIs has greater effect in the decrease of proteinuria, not attributable to effects on systemic blood pressure [28, 29]. In a large study of hypertensive patients with diabetic nephropathy and microalbuminuria, combined therapy resulted in greater reduction of blood pressure and albuminuria than did therapy with either drug alone [30]. In a Japanese study, in addition to decreased proteinuria, the slope of decline of glomerular filtration rate (GFR) improved with combination ACEI and ARB versus monotherapy [31]. However, complete dose-range comparisons of combined therapy with monotherapy were not made in these clinical trials. A recent review of clinical trials with combination therapy with ACEI and ARB in CKD patients support that such combination therapy had increased effects to decrease proteinuria without significantly increasing adverse side effects [16].

Antifibrotic effects of combination therapy versus monotherapy could include augmented bradykinin and AT2 activity and also decreased urinary transforming growth factor (TGF)-β [32]. In addition, there may be greater suppression of the renin–angiotensin system (RAS) with combined therapy, decreasing both ligand generation by inhibition of ACE and binding of any remaining AngII to the AT1 receptor. However, even suprapharmacological doses of ACE inhibition did not achieve complete suppression of the local RAS in experimental models [33]. Similarly, patients receiving ACEIs long term still have measurable ACE in their plasma. These data support the notion that non-ACE-dependent AngII generation by chymotrypsin-sensitive generating enzyme occurs in humans. New directions under investigation include the development of renin antagonists that could obviate these obstacles to optimal inhibition of the RAAS. Renin itself may have direct effects, independent of activation of the RAAS, with renin receptor activity detected on mesangial cells [34].

Many profibrotic actions of the RAAS are mediated directly by AngII. AngII promotes migration of endothelial and vascular smooth muscle cells, and hypertrophy and hyperplasia of smooth muscle cells and mesangial cells [35, 36]. All components of the RAS are present in macrophages, which may thus serve as yet another source of AngII and also respond to ACEI and ARB. AngII also induces other growth factors, including basic fibroblast growth factor (basic FGF), platelet-derived growth factor (PDGF) and TGF-β, and plasminogen activator inhibitor-1 (PAI-1), all of which may impact on fibrosis (see below), [37, 38, 39].

Importantly, new data indicate that aldosterone has both genomic and non-genomic actions to promote fibrosis, independent of its actions to increase blood pressure by mediating salt retention [40, 41]. Aldosterone enhances angiotensin induction of PAI-1 (see below), and also has direct actions on fibrosis [40]. Conversely, aldosterone receptor antagonism with spironolactone decreased injury [40]. PAI-1 deficiency prevented aldosterone-induced glomerular injury, but interestingly did not alter cardiac or aortic injury in this mouse model, suggesting site-specific and perhaps species-specific mechanisms of aldosterone-PAI-1 mediated fibrosis [42]. In clinical trials, aldosterone antagonism has further decreased proteinuria when added to ACEI and ARB therapy [43, 44]. However, the potential risk of hyperkalemia may limit the ability to add aldosterone antagonism to angiotensin inhibition. Whether these approaches also apply to children with CKD has not been investigated.

Clearly, the RAAS has many non-hemodynamic actions and thus, doses beyond usual antihypertensive doses are potentially of additional benefit. Regression has even been achieved in experimental models with high-dose ACEI/ARB. A shift in the balance of synthesis/degradation of extracellular matrix (ECM) must occur to accomplish regression of sclerosis; endothelial cells must regenerate, mesangial cells must regrow, and finally, podocytes must be restored. New glomeruli cannot be generated after term birth in humans. However, remaining segments of non-sclerotic loops can give rise to more open capillary area by lengthening or branching of the remaining capillaries [45, 46, 47, 48]. Recent experimental data show that regression can, indeed, be induced by high-dose ACEI or ARB or spironolactone, linked to decreased PAI-1, restored plasmin activity and capillary remodeling [25, 49, 50, 51]. Of note, regression was not associated with increased expression or activity of matrix metalloproteases-2 or -9 or decreased mRNA for TGF-β or local decreases in TGF-β expression as assessed by in situ hybridization. However, lack of changes in mRNA does not rule out that local changes in TGF-β actions could occur, and clearly, in many systems, TGF-β has been shown to impact on ECM accumulation. Regression is also possible in human CKD, demonstrated in principle by regression of early diabetic sclerosis and tubulointerstitial fibrosis in patients over a 10-year period when the underlying diabetes was cured by pancreas transplantation [52]. Regression of existing lesions also occurred in IgA nephropathy in response to high-dose corticosteroids and tonsillectomy [53].

Specific cytokines/growth factors and progression of CKD

Numerous cytokines/growth factors appear to modulate progression of glomerular and tubulointerstitial scarring. These factors and their roles may differ at the various stages of injury. Altered gene expressions and/or pharmacologic manipulations in pathophysiological settings have implicated e.g. PDGF, TGF-β, AngII, basic FGF, endothelin, various chemokines, peroxisome proliferator-activated receptor-γ (PPAR-γ) and PAI-1, among others, in progressive renal scarring [10, 54, 55, 56]. Current state-of-the-art approaches with proteomic and array analysis of renal tissue in human CKD and in animal models can identify novel targets and markers, and even mediators of progression [57, 58]. Of these many potential molecules of interest, we will discuss only a few that have been investigated in depth.

Increased PAI-1 is associated with increased cardiovascular disease and fibrotic kidney disease [59]. Conversely, PAI-1 could be decreased by inhibition of AngII and/or aldosterone, and linked to prevention of sclerosis or even regression of existing kidney fibrosis [25, 38, 51, 60]. AngII and aldosterone can also induce PAI-1 expression and subsequent fibrosis independent of TGF-β activation [61]. Some of the effects of PAI-1 in promoting fibrosis are independent of its effects on proteolysis. PAI-1 also modulates cell migration, perhaps by its effects on vitronectin interaction [59]. Thus, PAI-1 may in some inflammatory or interstitial disease settings increase fibrosis primarily by enhancing cell migration and epithelial-mesenchymal transition (EMT). In contrast, in the glomerulus, the effects of PAI-1 in the increase of sclerosis may predominantly be due to its ability to modulate ECM turnover [59]. These data support that mechanisms of fibrosis in the interstitium and glomerulus are not identical, and involve complex interactions of parenchymal and infiltrating cells and cytokines, with variable net effects on ECM accumulation.

TGF-β promotes ECM synthesis and is a key promoter of fibrosis. The biological actions of TGF-β are complex and depend not only on cell state, but also on the presence of decorin and latency-associated peptide (LAP), both of which can bind and modify its activity [37]. TGF-β also induces both PAI-1 and AngII [62]. Animals transgenic for TGF-β developed progressive renal disease [63]. Conversely, inhibition of either TGF-β or PDGF-B decreased mesangial matrix expansion in the anti-Thy1 model [64, 65]. Animals genetically deficient for TGF-β develop lymphoproliferative disease, thought to reflect a loss of TGF-β immune regulatory effect [66]. Interestingly, pharmacologic inhibition of TGF-β was more effective at lower dose, and with higher dose of anti-TGF-β associated with more fibrosis and greater macrophage influx, perhaps also reflecting effects on TGF-β immune modulation [67]. TGF-β may promote a more fibroblastic phenotype of the podocyte, with loss of differentiation markers and de novo expression of alpha-smooth muscle actin [68]. Although TGF-β promotes growth arrest and differentiation of podocytes at low doses, at higher doses, TGF-β causes podocyte apoptosis, mediated by Smad 7 signaling [69, 70]. Loss of podocytes (see below) is a key factor contributing to progressive kidney fibrosis.

PPAR-γ modifies numerous cytokines and growth factors, including PAI-1 and TGF-β. PPAR-γ is a transcription factor and a member of the steroid superfamily [71]. On activation, PPAR-γ binds the retinoic acid X receptor, translocates to the nucleus and binds to peroxisome proliferator activator response elements (PPREs) in selected target genes, modifying their expression. PPAR-γ agonists, such as the thiazolidinediones, are most commonly used to treat type 2 diabetes, due to their beneficial effects to increase insulin sensitivity and improve lipid metabolism, and they have been shown to decrease diabetic injury correspondingly in diabetic animal models [72]. Interestingly, PPAR-γ agonists also have antifibrotic effects in non-diabetic or non-hyperlipidemic experimental models of CKD. PPAR-γ agonist ameliorated the development of sclerosis in these non-diabetic models, linked to decreased PAI-1 and TGF-β and decreased infiltrating macrophages and protection of podocytes against injury [56, 73]. Further study is necessary to determine the specific role each of the above factors plays at varying stages of renal fibrosis.

Podocyte loss

Podocytes are the primary target in many glomerular diseases, including FSGS and the experimental models of adriamycin and puromycin aminonucleoside-induced nephropathies [74]. The podocytes are pivotal for maintenance of normal permselectivity, and are a source of matrix in both physiological and pathophysiological settings. The podocyte does not normally proliferate. Loss of podocytes after injury is postulated to be a key factor resulting in progressive sclerosis [74]. This principle was proven in experimental models in mice and rats, where podocyte-specific injury was produced by genetic manipulation of the podocytes to express toxin receptors only on this cell [75, 76]. Injection of toxin then resulted in podocyte loss, the degree of which depended on toxin dose. Animals subsequently developed progressive sclerosis. Of interest, even though only podocytes were initially injured, subsequent injury rapidly also developed in endothelial and mesangial cells, with resulting sclerosis. Even when chimeric mice were genetically engineered so that only a portion of their podocytes was susceptible to the toxin, all podocytes developed injury after toxin exposure [77]. These data show that injury can also spread from the initially injured podocyte to initially intact podocytes within a glomerulus, setting up a vicious cycle of progressive injury at the glomerular level [77].

The limited proliferation in the mature podocyte is accompanied by high expression of a cyclin-dependent kinase inhibitor, p27kip1, a rate-limiting step for the growth response of the podocyte [78]. Either too much or too little proliferation of the podocyte in response to genetic manipulation of p27kip1 is postulated be detrimental [79]. Inadequate growth of the podocyte is postulated to give rise to areas of dehiscence and insudation of plasma proteins, which progress to adhesions and sclerosis [80]. Another cyclin-dependent kinase inhibitor, p21, appears to be necessary for development of injury after five-sixths nephrectomy in mice, pointing to the crucial importance of cell growth responses in determining response to injury [81].

Podocytes normally produce an endogenous heparin-like substance, which inhibits mesangial cell growth; thus, injury may decrease this growth inhibitory effect and allow increased mesangial growth. Podocytes are also the main renal source of angiopoietin-1 and vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen that plays a key role in both physiologic and pathologic angiogenesis and vascular permeability [82]. Overexpression or partial loss of podocyte VEGF results in a collapsing lesion or pre-eclampsia-like endotheliosis lesion, respectively [82].

Podocyte genes and CKD

New studies of the molecular biology of the podocyte and identification of genes mutated in rare familial forms of FSGS and nephrotic syndrome, such as nephrin, WT-1, transient receptor potential cation channel-6 (TRPC-6), phospholipase C epsilon, α-actinin-4 and podocin, have given important new insights into mechanisms of progressive glomerulosclerosis. The gene mutated for congenital nephrotic syndrome, nephrin (NPHS1) is localized to the slit diaphragm of the podocyte and is tightly associated with CD2-associated protein (CD2AP) [83]. Nephrin functions as a zona occludens-type junction protein, and together with CD2AP, provides a crucial role in receptor patterning and cytoskeletal polarity and also provides signaling function of the slit diaphragm [84]. Mice with CD2AP knockout develop congenital nephrotic syndrome, similar to congenital nephrotic syndrome of Finnish type [85]. Autosomal dominant FSGS with adult onset is caused by mutation in α-actinin 4 (ACTN4) [86]. This is hypothesized to cause altered actin–cytoskeleton interaction, causing FSGS through a gain-of-function mechanism, in contrast to the loss-of-function mechanism implicated for disease caused by the nephrin mutation [85]. Patients with α-actinin 4 mutation progress to end-stage by age 30 years, with rare recurrence in a transplant. TRPC-6 encodes for a cation channel, which is present in several sites including podocytes. TRPC-6 is mutated in some kindreds with familial FSGS with adult onset in an autosomal dominant pattern [87]. Podocin, another podocyte-specific gene (NPHS2), is mutated in autosomal recessive FSGS with childhood onset with rapid progression to end-stage kidney disease [88]. Podocin interacts with the CD2AP-nephrin complex, indicating that podocin could serve in the structural organization of the slit diaphragm. In some series of steroid-resistant pediatric patients with non-familial forms of FSGS, a surprisingly high proportion, up to 25%, had podocin mutations [89, 90]. However, not all patients with nephrotic syndrome caused by mutation are steroid resistant. Diffuse mesangial sclerosis in a large kindred was recently linked to a truncating mutation of phospholipase C epsilon (PLCE1), and two of those patients responded to steroid therapy [91]. However, in two patients with missense mutation of this same gene, FSGS lesions developed, demonstrating that a spectrum of structural abnormalities may arise from varying mutations in the same gene. PLCE1 is expressed in the glomerulus, where it is postulated to play a key role in development, perhaps by interacting with other proteins that are crucial for the development and function of the slit diaphragm.

WT-1 mutation, which may occur sporadically with only FSGS or be associated with Denys–Drash syndrome, was found in only 5% of steroid-resistant patients [92]. Interestingly, mutations of podocin or WT-1 were not found in relapsing or steroid-dependent pediatric patients [93]. Acquired disruption or polymorphisms of some of these complexly interacting molecules have been demonstrated in experimental models and in human proteinuric diseases. Thus, in puromycin aminonucleoside nephropathy, a model of FSGS, nephrin localization and organization were altered [94]. Similar decreases in nephrin were observed in hypertensive diabetic rat models with significant proteinuria [95]. TRPC-6, a calcium channel, was induced in various non-genetic human proteinuric diseases [96]. Conversely, treatments that ameliorated these experimental models preserved e.g. glomerular nephrin expression, providing further support for a key causal role for slit diaphragm and key podocyte molecules in proteinuria [97]. Whether polymorphisms, compound heterozygosity for mutations or merely altered distribution and/or expression of any of these proteins contribute to proteinuria or progressive disease in various causes of CKD in humans has not been determined.


Patients with CKD frequently have dyslipidemia and greatly increased cardiovascular disease risk, even beyond that predicted by lipid abnormalities [98]. Abnormal lipids are important in modulating glomerular sclerosis in rats; however, analogous studies in humans are still evolving [99, 100, 101, 102]. Glomerular injury was increased in experimental CKD when excess cholesterol was added to the diets. Glomerular disease has been reported in the rare familial disease, lecithin cholesterol acyltransferase deficiency, and with excess apolipoprotein E. However, renal disease is not typical in the more common forms of primary hyperlipidemias. Patients with minimal-change disease or membranous glomerulonephritis, characterized by hyperlipidemia as part of their nephrotic syndrome, usually do not develop glomerular scarring. However, recently, post hoc and meta-analyses of clinical trial data support that abnormal lipids are associated with increased loss of GFR and that treatment with statins may not only benefit cardiovascular disease risk, but also be of benefit for progressive CKD. A post hoc analysis suggests that statins may even slow progression in patients with stage 3 CKD [102]. These beneficial effects of statins appear to extend beyond their lipid-lowering effects [98, 101].


Proteinuria is a marker of renal injury, reflecting loss of normal permselecitvity. Further, proteinuria itself has been proposed to contribute to progressive renal injury inflammation [74, 103]. Increased proteinuria is associated with worse prognosis [104]. Whether proteinuria is merely a marker of injury or a contributor to progressive injury has been debated.

Albumin can in vitro in tubular cells increase AngII and in turn upregulate TGF-β receptor expression [105]. However, in most settings, pure albumin per se is not directly injurious. Other filtered components of the urine in proteinuric states, such as oxidized proteins, appear to be more potent in inducing direct injury of tubular epithelial cells and activating proinflammatory and fibrotic chemokines and cytokines. Complement and various lipoproteins are also present in the urine in proteinuric disease states and can activate reactive oxygen species [101, 106]. Proteinuria may thus alter tubule cell function directly, potentially contributing to a more profibrotic phenotype, and also augment interstitial inflammation, in particular by macrophages. Proteinuria may activate many profibrotic pathways through its ability to increase NF-kB, and also by other pathways. These include for instance complement synthesis from tubules [107].

Interventions that are particularly effective in decreasing proteinuria, such as the administration of ACEIs or ARBs, also decrease overall end organ injury. Whether these beneficial effects are dependent on the reduction of proteinuria has not been proven, in that these interventions have multiple parallel effects that may all contribute to the decrease of fibrosis [107].

Mechanisms of tubulointerstitial fibrosis

Tubulointerstitial fibrosis classically was thought merely to reflect glomerular injury and resulting whole nephron ischemia in most CKD. Interesting new data point to independent mechanisms of interstitial fibrosis and the importance of the tubulointerstitial lesion in progression. Decreased peritubular capillary density, possibly modulated by decreased VEGF or other angiogenic factors, has been proposed as a mechanism in various progressive renal diseases [108]. Future studies may demonstrate whether these interstitial microvascular lesions are causal or consequential in the development of interstitial injury.

Increased numbers of macrophages are closely correlated with both glomerulosclerosis and tubulointerstitial fibrosis and are usually decreased by interventions that decrease fibrosis. These cells are potential sources of numerous cytokines and eicosanoids that affect the glomerulus [109]. Support for this hypothesis is seen with the protective effects of maneuvers that decrease macrophage influx. In a rat model of unilateral ureteral obstruction (UUO), administration of ACEI ameliorated interstitial monocyte/macrophage infiltration and decreased fibrosis [110]. Studies in β6 integrin-deficient mice revealed that infiltrating macrophages do not inevitably transduce fibrotic effects; in these mice local activation of TGF-β is impaired, and they are protected from fibrosis despite abundant macrophage infiltration [61]. Macrophages may even play a beneficial role in scarring. The specific role of the macrophage AT1a receptor in renal fibrosis was examined in studies of bone marrow transplantation in wild type mice with UUO mice reconstituted with either wild type macrophages or macrophages devoid of the AT1a receptor. There was more severe interstitial fibrosis in mice with the AT1a deficient macrophages, even though fewer infiltrating macrophages were observed, suggesting that the macrophage AT1a receptor functions to protect the kidney from fibrogenesis [111].

In human diabetic nephropathy there is an early increase in total interstitial cell volume (which may represent increased cell size and/or number), preceding the accumulation of interstitial collagen [112]. This is in contrast to the diabetic glomerular lesion, where the expanded mesangial area is largely due to increased matrix accumulation rather than hypercellularity. These interstitial cells could possibly represent interstitial myofibroblasts, postulated to play a key role in interstitial fibrosis. These activated interstitial cells are a major source of collagen synthesis, and increased expression of α-smooth muscle actin (SMA), a marker of myofibroblasts, predicts progressive renal dysfunction both in human and experimental renal disease.

The source of interstitial myofibroblasts is a topic of controversy. Bone marrow-derived or potential renal stem cells may give rise not only to interstitial cells but also to regenerating parenchymal cells [113]. Epithelial–mesenchymal transformation (EMT) is another possible mechanism for generation of interstitial myofibroblasts [114]. This seamless plasticity of cells changing from epithelial to mesenchymal phenotypes exists during early development. EMT may also occur in the adult after injury, contributing approximately half of the interstitial fibroblasts in experimental models [114]. Injured tubular epithelial cells can change phenotype both in vivo and in vitro, with de novo expression of a fibroblast-specific protein (FSP1), and possibly migrate into the interstitium as myofibroblasts. The surrounding matrix and basement membrane underlying the tubular epithelium is disrupted by local proteolysis, modulated by an array of cytokines and growth factors, including insulin-like growth factors I and II, integrin-linked kinases, EGF, FGF-2 and TGF-β [114]. Several key factors inhibit EMT, including hepatocyte growth factor and bone morphogenetic factor-7, and thus inhibit fibrosis in experimental CKD [114].

Anatomic and genetic risks for CKD: nephron number and gene polymorphisms

Risk for development of CKD and its rate of progression varies in differing populations. CKD associated with hypertension and arterio-nephrosclerosis is particularly common in African Americans, and FSGS is more frequently the underlying cause of steroid-resistant FSGS in African Americans and Hispanics than in Caucasians [115, 116]. These varying disease trends in differing ethnic populations could represent both genetic and environmental factors. Low birth weight is epidemiologically linked to increased risk for cardiovascular disease, hypertension and CKD in adulthood. The link is postulated to be due to the decreased nephron number that accompanies low term birth weight, defined as less than 2,500 g [117, 118]. These fewer nephrons are postulated to be under greater hemodynamic stress, thus contributing to progressive sclerosis. Of interest, low birth weight is much more common in African Americans than in Caucasians and is not accounted for by socioeconomic status [119]. Further, glomerular size in normal African Americans is larger than in Caucasians and could possibly reflect smaller nephron number [120]. In Australian Aborigines, marked increase in incidence of CKD is associated with larger but fewer glomeruli and low birth weight [121, 122]. Mechanisms other than hemodynamic stress that could underlie these differences in normal glomerular populations and also relate to increased incidence of end-stage renal disease include functional polymorphisms of genes that are involved both in renal/glomerular development and contribute to amplified scarring mechanisms, such as the renin–angiotensin system [10].

African Americans also have increased severity of renal disease associated with several systemic conditions. The course of lupus nephritis in a prospective trial was more severe in African Americans than in Caucasians, with more extensive crescent formation and interstitial fibrosis and greater likelihood of end-stage renal disease [123]. Even the manifestations of HIV infection in the kidney differ markedly between African Americans and Caucasians: HIV-associated renal disease in African Americans is typically an aggressive collapsing type of FSGS, contrasting lower grade immune-complex-mediated glomerulonephritides in Caucasians with HIV infection and renal disease [124]. Genetic background also modulates susceptibility in experimental models, both to podocyte injury (e.g. only the balb/c mouse strain is susceptible to adriamycin) and to hypertension injury (e.g. in the five-sixths nephrectomy model, C57Bl mice are resistant, 129Sv/J mice are susceptible) and even to diabetic injury [125, 126, 127].

There is also accumulating evidence that specific genes in humans modulate the course and rate of organ damage. Polymorphisms in several genes within the RAAS system, including ACE, angiotensinogen and the angiotensin type 1 receptor, have been linked with cardiovascular and renal disorders, including diabetic nephropathy, IgA nephropathy and uropathies [128, 129, 130, 131, 132, 133]. The ACE DD genotype, associated with increased RAS activity, was increased in patients with IgA nephropathy who ultimately experienced progressive decline in renal function during follow-up compared with those whose function remained stable over the same time [134].

Polymorphisms of TGF-β are also implicated in hypertension and progressive fibrosis. The Arg 25 polymorphism may be increased in African Americans, who may also have greater elevation of circulating TGF-β when they reach end-stage renal disease than do Caucasians [135].

These observations suggest that complex genetic traits can modulate the response of glomerular cells to pathogenic stimuli in experimental models. Whether ethnic differences in development of renal disease in humans reflect contributions of genetic and/or environmental influences remains to be definitively determined.

QUESTIONS (Answers appear following the reference list)
  1. 1.
    A 6-year-old African American boy presented with generalized edema, 24 h urine protein excretion of 1.5 g and normal complements, and serum creatinine of 0.7 mg/dl. His blood pressure was 110/70 mmHg. His nephrotic syndrome did not respond to an 8-week course of steroids, and a renal biopsy is planned. The most likely diagnosis in this patient is:
    1. (a)

      FSGS due to mutation of podocin

    2. (b)

      Minimal-change disease

    3. (c)

      FSGS, usual type

    4. (d)

      Diffuse mesangial sclerosis

    5. (e)

      Collapsing glomerulopathy

  2. 2.
    For the same patient detailed in question 1, what additional treatment should be initiated at this time to decrease risk of CKD:
    1. (a)


    2. (b)


    3. (c)


    4. (d)

      Beta blockers

    5. (e)

      ACEIs and ARBs

  3. 3.
    In the same patient detailed in the above questions, what parameters would be most important to follow and evaluate for adjustment of therapy:
    1. (a)


    2. (b)

      White blood cell (WBC) count

    3. (c)

      Blood pressure

    4. (d)


  4. 4.
    A 14-year-old Caucasian girl was diagnosed with IgA nephropathy, which on biopsy showed fibrocellular crescents, with focal proliferative and secondary sclerosing lesions of glomeruli. Her urine protein excretion was 1.0 g in 24 h. Urinalysis showed frequent red blood cell casts, serum creatinine was 1.2 mg/dl and her blood pressure was 120/93 mmHg. Which of the following mechanisms are likely to contribute to progression of her CKD:
    1. (a)

      Podocyte loss

    2. (b)


    3. (c)

      Glomerular hypertension

    4. (d)

      Infiltrating macrophages

    5. (e)

      All of the above

  5. 5.
    A 10-year-old Caucasian boy with a history of multiple episodes of steroid-dependent nephrotic syndrome since the age of 4 years now has proteinuria of 3.8 g in 24 h, with unremarkable urinalysis without red blood cell casts; his serum creatinine is 0.6 mg/dl, and his blood pressure is 98/64 mmHg. He has an increased cholesterol level of 480 mg/dl and triglyceride levels are 110 mg/dl. What mechanisms of renal injury are likely to be activated in this child:
    1. (a)

      podocyte loss

    2. (b)


    3. (c)


    4. (d)

      glomerular hypertension

    5. (e)

      (b) and (c)




This work was supported in part by NIH grants DK 44757 and DK 56942.


  1. 1.
    Foreman JW, Chan JC (1988) Chronic renal failure in infants and children. J Pediatr 113:793–800PubMedGoogle Scholar
  2. 2.
    Drummond K, Mauer M, International Diabetic Nephropathy Study Group (2002) The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes 51:1580–1587PubMedGoogle Scholar
  3. 3.
    Olson JL, Heptinstall RH (1988) Nonimmunologic mechanisms of glomerular injury. Lab Invest 59:564–578PubMedGoogle Scholar
  4. 4.
    Morrison AB, Howard RM (1966) The functional capacity of hypertrophied nephrons: effect of partial nephrectomy on the clearance of inulin and PAH in the rat. J Exp Med 123:829–844PubMedGoogle Scholar
  5. 5.
    Shimamura T, Morrison AB (1975). A progressive glomerulosclerosis occurring in partial five-sixths nephrectomized rats. Am J Pathol 79:95–106PubMedGoogle Scholar
  6. 6.
    Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM (1981) Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 241:F85–F93PubMedGoogle Scholar
  7. 7.
    Grond J, Weening JJ, Elema JD (1984) Glomerular sclerosis in nephrotic rats. Comparison of the long-term effects of adriamycin and aminonucleoside. Lab Invest 51:277–285PubMedGoogle Scholar
  8. 8.
    Brenner BM, Meyer TW, Hostetter TH (1982) Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 307:652–659PubMedCrossRefGoogle Scholar
  9. 9.
    Nath KA, Kren SM, Hostetter TH (1986) Dietary protein restriction in established renal injury in the rat. Selective role of glomerular capillary pressure in progressive glomerular dysfunction. J Clin Invest 78:1199–1205PubMedGoogle Scholar
  10. 10.
    Fogo AB (2000) Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases. Kidney Int Suppl 75:S15–21PubMedGoogle Scholar
  11. 11.
    Kakinuma Y, Kawamura T, Bills T, Yoshioka T, Ichikawa I, Fogo A (1992) Blood-pressure independent effect of angiotensin inhibition on vascular lesions of chronic renal failure. Kidney Int 42:46–55PubMedGoogle Scholar
  12. 12.
    Kon V, Fogo A, Ichikawa I (1993) Bradykinin causes selective efferent arteriolar dilatation during angiotensin I converting enzyme inhibition. Kidney Int 44:545–550PubMedGoogle Scholar
  13. 13.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 330:1456–1462Google Scholar
  14. 14.
    Kasiske BL, Kalil RS, Ma JZ, Liao M, Keane WF (1993) The effect of blood pressure treatment on the kidney in diabetes: a meta-regression analysis. Ann Intern Med 118:129–138PubMedGoogle Scholar
  15. 15.
    Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P (1996) Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334:939–945PubMedGoogle Scholar
  16. 16.
    MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD (2006) Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 48:8–12PubMedGoogle Scholar
  17. 17.
    Yamada T, Horiuchi T, Dzau VJ (1996) Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA 93:156–160PubMedGoogle Scholar
  18. 18.
    Stoll M, Steckelings M, Paul M, Bottari SP, Metzger R, Unger T (1995) The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 95:651–657PubMedGoogle Scholar
  19. 19.
    Steckelings UM, Kaschina E, Unger T (2005) The AT2 receptor–a matter of love and hate. Peptides 26:1401–1409PubMedGoogle Scholar
  20. 20.
    Siragy HM (2000) AT(1) and AT(2) receptors in the kidney: role in disease and treatment. Am J Kidney Dis 36 [3 Suppl 1]:S4–9PubMedGoogle Scholar
  21. 21.
    Ma J, Nishimura H, Fogo A, Kon V, Inagami T, Ichikawa I (1998) Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. Kidney Int 53:937–944PubMedGoogle Scholar
  22. 22.
    Ohkubo N, Matsubara H, Nozawa Y, Mori Y, Murasawa S, Kijima K, Maruyama K, Masaki H, Tsutumi Y, Shibazaki Y, Iwasaka T, Inada M (1997) Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation 96:3954–3962PubMedGoogle Scholar
  23. 23.
    Wolf G, Ritz E (2005) Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 67:799–812PubMedGoogle Scholar
  24. 24.
    Ots M, Mackenzie HS, Troy JL, Rennke HG, Brenner BM (1998) Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation. J Am Soc Nephrol 9:224–230PubMedGoogle Scholar
  25. 25.
    Ma L-J, Nakamura S, Aldigier JC, Rossini M, Yang H, Liang X, Nakamura I, Marcantoni C, Fogo AB (2005) Regression of glomerulosclerosis with high dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1. J Am Soc Nephrol 16:966–976PubMedGoogle Scholar
  26. 26.
    Naito T, Ma L, Donnert E, Fogo AB (2005) Angiotensin type 2 receptor antagonist (AT2RA) worsens glomerulosclerosis in the rat remnant kidney model. J Am Soc Nephrol 16:654AGoogle Scholar
  27. 27.
    Hashimoto N, Maeshima Y, Satoh M, Odawara M, Sugiyama H, Kashihara N, Matsubara H, Yamasaki Y, Makino H (2004) Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model. Am J Physiol Renal Physiol 286:F516–F525PubMedGoogle Scholar
  28. 28.
    Russo D, Pisani A, Balletta MM, De Nicola L, Savino FA, Andreucci M, Minutolo R (1999) Additive antiproteinuric effect of converting enzyme inhibtion and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 33:851–856PubMedGoogle Scholar
  29. 29.
    Hebert LA, Falkenhain ME, Nahman NS Jr, Cosio FG, O’Dorisio TM (1999) Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy. Am J Nephrol 19:1–6PubMedGoogle Scholar
  30. 30.
    Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME (2000) Randomised controlled trial of dual blockade of renin–angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 321:1440–1444PubMedGoogle Scholar
  31. 31.
    Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361:117–124PubMedGoogle Scholar
  32. 32.
    Taal MW, Brenner BM (2002) Combination ACEI and ARB therapy: additional benefit in renoprotection? Curr Opin Nephrol Hypertens 11:377–381PubMedGoogle Scholar
  33. 33.
    Nishiyama A, Seth DM, Navar LG (2002) Renal interstitial fluid concentrations of angiotensins I and II in anesthetized rats. Hypertension 39:129–134PubMedGoogle Scholar
  34. 34.
    Azizi M, Webb R, Nussberger J, Hollenberg NK (2006) Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 24:243–256PubMedGoogle Scholar
  35. 35.
    Orth SR, Weinreich T, Bönisch S, Weih M, Ritz E (1995) Angiotensin II induces hypertrophy and hyperplasia in adult human mesangial cells. Exp Nephrol 3:23–33PubMedGoogle Scholar
  36. 36.
    Wolf G, Neilson EG (1993) Angiotensin II as a renal growth factor. J Am Soc Nephrol 3:1531–1540PubMedGoogle Scholar
  37. 37.
    Ketteler M, Noble NA, Border WA (1995) Transforming growth factor-b and angiotensin II: The missing link from glomerular hyperfiltration to glomerulosclerosis? Annu Rev Physiol 57:279–295PubMedGoogle Scholar
  38. 38.
    Oikawa T, Freeman M, Lo W, Vaughan DE, Fogo A (1997) Modulation of plasminogen activator inhibitor-1 (PAI-1) in vivo: a new mechanism for the anti-fibrotic effect of renin–angiotensin inhibition. Kidney Int 51:164–172PubMedGoogle Scholar
  39. 39.
    Nakamura S, Nakamura I, Ma L, Vaughan DE, Fogo AB (2000) Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo. Kidney Int 58:251–259PubMedGoogle Scholar
  40. 40.
    Brown NJ (2005) Aldosterone and end-organ damage. Curr Opin Nephrol Hypertens 14:235–241PubMedGoogle Scholar
  41. 41.
    Epstein M (2006) Aldosterone blockade: an emerging strategy for abrogating progressive renal disease. Am J Med 119:912–919PubMedGoogle Scholar
  42. 42.
    Ma J, Weisberg A, Griffin JP, Vaughan DE, Fogo AB, Brown NJ (2006) Plasminogen activator inhibitor-1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int 69:1064–1072PubMedGoogle Scholar
  43. 43.
    Bianchi S, Bigazzi R, Campese VM (2006) Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 70:2116–2123PubMedGoogle Scholar
  44. 44.
    Weinberger MH, Luft FC (2006) Comprehensive suppression of the renin–angiotensin–aldosterone system in chronic kidney disease: covering all of the bases. Kidney Int 70:2051–2053PubMedGoogle Scholar
  45. 45.
    Nyengaard JR (1993) Number and dimensions of rat glomerular capillaries in normal development and after nephrectomy. Kidney Int 43:1049–1057PubMedGoogle Scholar
  46. 46.
    Marcussen N, Nyengaard JR, Christensen S (1994) Compensatory growth of glomeruli is accomplished by an increased number of glomerular capillaries. Lab Invest 70:868–874PubMedGoogle Scholar
  47. 47.
    Nyengaard JR, Rasch R (1993) The impact of experimental diabetes mellitus in rats on glomerular capillary number and sizes. Diabetologia 36:189–194PubMedGoogle Scholar
  48. 48.
    Akaoka K, White RHR, Raafat F (1995) Glomerular morphometry in childhood reflux nephropathy, emphasizing the capillary changes. Kidney Int 47:1108–1114PubMedGoogle Scholar
  49. 49.
    Adamczak M, Gross ML, Krtil J, Koch A, Tyralla K, Amann K, Ritz E (2003) Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. J Am Soc Nephrol 14:2833–2842PubMedGoogle Scholar
  50. 50.
    Adamczak M, Gross ML, Amann K, Ritz E (2004) Reversal of glomerular lesions involves coordinated restructuring of glomerular microvasculature. J Am Soc Nephrol 15:3063–3072PubMedGoogle Scholar
  51. 51.
    Aldigier JC, Kanjanabuch T, Ma L-J, Brown NJ, Fogo AB (2005) Regression of existing glomerulosclerosis by inhibition of aldosterone. J Am Soc Nephrol 16:3306–3314PubMedGoogle Scholar
  52. 52.
    Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M (1998) Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69–75PubMedGoogle Scholar
  53. 53.
    Hotta O, Furuta T, Chiba S, Tomioka S, Taguma Y (2002) Regression of IgA nephropathy: a repeat biopsy study. Am J Kidney Dis 39:493–502PubMedGoogle Scholar
  54. 54.
    Fine LG, Hammerman MR, Abboud HE (1992) Evolving role of growth factors in the renal response to acute and chronic disease. J Am Soc Nephrol 2:1163–1170PubMedGoogle Scholar
  55. 55.
    Kashgarian M, Sterzel RB (1992) The pathobiology of the mesangium. Kidney Int 41:524–529PubMedGoogle Scholar
  56. 56.
    Yang HC, Ma LJ, Ma J, Fogo AB (2006) Peroxisome proliferator-activated receptor-gamma agonist is protective in podocyte injury-associated sclerosis. Kidney Int 69:1756–1764PubMedGoogle Scholar
  57. 57.
    Schmid H, Henger A, Kretzler M (2006) Molecular approaches to chronic kidney disease. Curr Opin Nephrol Hypertens 15:123–129PubMedGoogle Scholar
  58. 58.
    Xu BJ, Shyr Y, Liang X, Ma LJ, Donnert EM, Roberts JD, Zhang X, Kon V, Brown NJ, Caprioli RM, Fogo AB (2005) Proteomic patterns and prediction of glomerulosclerosis and its mechanisms. J Am Soc Nephrol 16:2967–2975PubMedGoogle Scholar
  59. 59.
    Eddy AA, Fogo AB (2006) Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action. J Am Soc Nephrol 17:2999–3012PubMedGoogle Scholar
  60. 60.
    Brown NJ, Kim KS, Chen YQ, Blevins LS, Nadeau JH, Meranze SG, Vaughan DE (2000) Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 expression. J Clin Endocrinol Metab 85:336–344PubMedGoogle Scholar
  61. 61.
    Ma LJ, Yang H, Gaspert A, Carlesso G, Barty MM, Davidson JM, Sheppard D, Fogo AB (2003) Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(−/−) mice. Am J Pathol 163:1261–1273PubMedGoogle Scholar
  62. 62.
    Gaedeke J, Peters H, Noble NA, Border WA (2001) Angiotensin II, TGF-beta and renal fibrosis. Contrib Nephrol 135:153–160PubMedGoogle Scholar
  63. 63.
    Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP, Klotman PE, Thorgeirsson SS (1996) Transgenic mice with increased levels of TGF-β1 develop progressive renal disease. Lab Invest 74:991–1003PubMedGoogle Scholar
  64. 64.
    Johnson RJ, Raines EW, Floege J, Yoshimura A, Pritzl P, Alpers C, Ross R (1992) Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med 175:1413–1416PubMedGoogle Scholar
  65. 65.
    Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E (1990) Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 346:371–374PubMedGoogle Scholar
  66. 66.
    Christ M, McCartney-Francis NL, Kulkarni AB, Ward JM, Mizel DE, Mackall CL, Gress RE, Hines KL, Tian H, Karlsson S, Wahl SM (1994) Immune dysregulation in TGF-beta 1-deficient mice. J Immunol 153:1936–1946PubMedGoogle Scholar
  67. 67.
    Ma L-J, Sharda J, Hong Ling H, Pozzi A, Ledbetter S, Fogo AB (2004) Divergent effects of low vs high dose anti-TGF-β antibody in puromycin aminonucleoside nephropathy in rats. Kidney Int 65:106–115PubMedGoogle Scholar
  68. 68.
    Sam R, Wanna L, Gudehithlu KP, Garber SL, Dunea G, Arruda JA, Singh AK (2006) Glomerular epithelial cells transform to myofibroblasts: early but not late removal of TGF-beta1 reverses transformation. Transl Res 148:142–148PubMedGoogle Scholar
  69. 69.
    Schiffer M, Bitzer M, Roberts IS, Kopp JB, ten Dijke P, Mundel P, Bottinger EP (2001) Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 108:807–816PubMedGoogle Scholar
  70. 70.
    Wu DT, Bitzer M, Ju W, Mundel P, Bottinger EP (2005) TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J Am Soc Nephrol 16:3211–3221PubMedGoogle Scholar
  71. 71.
    Guan Y, Breyer MD (2001) Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease. Kidney Int 60:14–30PubMedGoogle Scholar
  72. 72.
    Buckingham RE, Al-Barazanji KA Toseland CD, Slaughter M, Connor SC, West A, Bond B, Turner NC, Clapham JC (1998) Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47:1326–1334PubMedGoogle Scholar
  73. 73.
    Ma LJ, Marcantoni C, Linton MF, Fazio S, Fogo AB (2001) Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats. Kidney Int 59:1899–1910PubMedGoogle Scholar
  74. 74.
    Shankland SJ (2006) The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 69:2131–2147PubMedGoogle Scholar
  75. 75.
    Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB, Wiggins RC (2005) Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 16:2941–2952PubMedGoogle Scholar
  76. 76.
    Matsusaka T, Xin J, Niwa S, Kobayashi K, Akatsuka A, Hashizume H, Wang QC, Pastan I, Fogo AB, Ichikawa I (2005) Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury. J Am Soc Nephrol 16:1013–1023PubMedGoogle Scholar
  77. 77.
    Ichikawa I, Ma J, Motojima M, Matsusaka T (2005) Podocyte damage damages podocytes: autonomous vicious cycle that drives local spread of glomerular sclerosis. Curr Opin Nephrol Hypertens 14:205–210PubMedCrossRefGoogle Scholar
  78. 78.
    Combs HL, Shankland SJ, Setzer SV, Hudkins KL, Alpers CE (1998) Expression of the cyclin kinase inhibitor, p27kip1, in developing and mature human kidney. Kidney Int 53:892–896PubMedGoogle Scholar
  79. 79.
    Shankland SJ (1999) Cell cycle regulatory proteins in glomerular disease. Kidney Int 56:1208–1215PubMedGoogle Scholar
  80. 80.
    Kriz W, Gretz N, Lemley KV (1998) Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 54:687–697PubMedGoogle Scholar
  81. 81.
    Megyesi J, Price PM, Tamayo E, Safirstein RL (1999) The lack of a functional p21(WAF1/CIP1) gene ameliorates progression to chronic renal failure. Proc Natl Acad Sci USA 96:10830–10835PubMedGoogle Scholar
  82. 82.
    Eremina V, Quaggin SE (2004) The role of VEGF-A in glomerular development and function. Curr Opin Nephrol Hypertens 13:9–15PubMedGoogle Scholar
  83. 83.
    Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestila M, Jalanko H, Holmberg C, Tryggvason K (1999) Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci USA 96:7962–7967PubMedGoogle Scholar
  84. 84.
    Huber TB, Benzing T (2005) The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens 14:211–216PubMedGoogle Scholar
  85. 85.
    Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286:312–315PubMedGoogle Scholar
  86. 86.
    Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR (2000) Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24:251–256PubMedGoogle Scholar
  87. 87.
    Winn MP, Daskalakis N, Spurney RF, Middleton JP (2006) Unexpected role of TRPC6 channel in familial nephrotic syndrome: does it have clinical implications? J Am Soc Nephrol 17:378–387PubMedGoogle Scholar
  88. 88.
    Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354PubMedGoogle Scholar
  89. 89.
    Karle SM, Uetz B, Ronner V, Glaeser L, Hildebrandt F, Fuchshuber A (2002) Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 13:388–393PubMedGoogle Scholar
  90. 90.
    Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F, Arbeitsgemeinschaft Für Padiatrische Nephrologie Study Group (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15:722–732PubMedGoogle Scholar
  91. 91.
    Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O’toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405PubMedGoogle Scholar
  92. 92.
    Mucha B, Ozaltin F, Hinkes BG, Hasselbacher K, Ruf RG, Schultheiss M, Hangan D, Hoskins BE, Everding AS, Bogdanovic R, Seeman T, Hoppe B, Hildebrandt F, Members of the APN Study Group (2006) Mutations in the Wilms’ tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9. Pediatr Res 59:325–331PubMedGoogle Scholar
  93. 93.
    Gbadegesin R, Hinkes B, Vlangos C, Mucha B, Liu J, Hopcian J, Hildebrandt F (2007) Mutational analysis of NPHS2 and WT1 in frequently relapsing and steroid-dependent nephrotic syndrome. Pediatr Nephrol 22:509–513PubMedGoogle Scholar
  94. 94.
    Kawachi H, Koike H, Kurihara H, Yaoita E, Orikasa M, Shia MA, Sakai T, Yamamoto T, Salant DJ, Shimizu F (2000) Cloning of rat nephrin: expression in developing glomeruli and in proteinuric states. Kidney Int 57:1949–1961PubMedGoogle Scholar
  95. 95.
    Forbes JM, Bonnet F, Russo LM, Burns WC, Cao Z, Candido R, Kawachi H, Allen TJ, Cooper ME, Jerums G, Osicka TM (2002) Modulation of nephrin in the diabetic kidney: association with systemic hypertension and increasing albuminuria. J Hypertens 20:985–992PubMedGoogle Scholar
  96. 96.
    Moller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, Pippin JW, Rastaldi MP, Wawersik S, Schiavi S, Henger A, Kretzler M, Shankland SJ, Reiser J (2007) Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol 18:29–36PubMedGoogle Scholar
  97. 97.
    Benigni A, Tomasoni S, Gagliardini E, Zoja C, Grunkemeyer JA, Kalluri R, Remuzzi G (2001) Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis. J Am Soc Nephrol 12:941–948PubMedGoogle Scholar
  98. 98.
    Cases A, Coll E (2005) Dyslipidemia and the progression of renal disease in chronic renal failure patients. Kidney Int Suppl 99:S87–93PubMedGoogle Scholar
  99. 99.
    Keane WF, Mulcahy WS, Kasiske BL, Kim Y, O’Donnell MP (1991) Hyperlipidemia and progressive renal disease. Kidney Int 39 [Suppl 31]:S41–S48Google Scholar
  100. 100.
    Oda H, Keane WF (1999) Recent advances in statins and the kidney. Kidney Int Suppl 71:S2–S5PubMedGoogle Scholar
  101. 101.
    Fried LF, Orchard TJ, Kasiske BL (2001) Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 59:260–269PubMedGoogle Scholar
  102. 102.
    Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC; Cholesterol and Recurrent Events Trial Investigators (2003) Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 14:1605–1613PubMedGoogle Scholar
  103. 103.
    Remuzzi G, Bertani T (1990) Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules? Kidney Int 38:384–394PubMedGoogle Scholar
  104. 104.
    Ruggenenti P, Remuzzi G (2006) Time to abandon microalbuminuria? Kidney Int 70:1214–1222PubMedGoogle Scholar
  105. 105.
    Wolf G, Schroeder R, Ziyadeh FN, Stahl RA (2004) Albumin up-regulates the type II transforming growth factor-beta receptor in cultured proximal tubular cells. Kidney Int 66:1849–1858PubMedGoogle Scholar
  106. 106.
    Perico N, Codreanu I, Schieppati A, Remuzzi G (2005) Pathophysiology of disease progression in proteinuric nephropathies. Kidney Int Suppl 94:S79–S82PubMedGoogle Scholar
  107. 107.
    Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17:2974–2984PubMedGoogle Scholar
  108. 108.
    Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ (2002) Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13:806–816PubMedGoogle Scholar
  109. 109.
    Kipari T, Hughes J (2002) Macrophage-mediated renal cell death. Kidney Int 61:760–761PubMedGoogle Scholar
  110. 110.
    Ishidoya S, Morrissey J, McCracken R, Reyes A, Klahr S (1995) Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 47:1285–1294PubMedGoogle Scholar
  111. 111.
    Nishida M, Fujinaka H, Matsusaka T, Price J, Kon V, Fogo AB, Davidson JM, Linton MF, Fazio S, Homma T, Yoshida H, Ichikawa I (2002) Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis. J Clin Invest 110:1859–1868PubMedGoogle Scholar
  112. 112.
    Katz A, Caramori ML, Sisson-Ross S, Groppoli T, Basgen JM, Mauer M (2002) An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients. Kidney Int 61:2058–2066PubMedGoogle Scholar
  113. 113.
    Al-Awqati Q, Oliver JA (2002) Stem cells in the kidney. Kidney Int 61:387–395PubMedGoogle Scholar
  114. 114.
    Neilson EG (2006) Mechanisms of disease: fibroblasts—a new look at an old problem. Nat Clin Pract Nephrol 2:101–108PubMedGoogle Scholar
  115. 115.
    Fogo AB (2003) Hypertensive risk factors in kidney disease in African Americans. Kidney Int 63 Suppl 83:S17–S21Google Scholar
  116. 116.
    Andreoli SP (2004) Racial and ethnic differences in the incidence and progression of focal segmental glomerulosclerosis in children. Adv Ren Replace Ther 11:105–109PubMedGoogle Scholar
  117. 117.
    Barker DJ, Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1:1077–1081PubMedGoogle Scholar
  118. 118.
    Brenner BM, Garcia DL, Anderson S (1988) Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens 1:335–347PubMedGoogle Scholar
  119. 119.
    Kleinman JC, Kessel SS (1987) Racial differences in low birth weight. Trends and risk factors. N Engl J Med 317:749–753PubMedGoogle Scholar
  120. 120.
    Pesce C, Schmidt K, Fogo A, Okoye MI, Kim R, Striker LJ, Striker GE (1994) Glomerular size and the incidence of renal disease in African Americans and Caucasians. J Nephrol 7:355–358Google Scholar
  121. 121.
    Hoy WE, Hughson MD, Singh GR, Douglas-Denton R, Bertram JF (2006) Reduced nephron number and glomerulomegaly in Australian Aborigines: a group at high risk for renal disease and hypertension. Kidney Int 70:104–110PubMedGoogle Scholar
  122. 122.
    Douglas-Denton RN, McNamara BJ, Hoy WE, Hughson MD, Bertram JF (2006) Does nephron number matter in the development of kidney disease? Ethn Dis 16 [2 Suppl 2]:S240–S245Google Scholar
  123. 123.
    Austin HA, Boumpas DT, Vaughan EM, Balow JE (1995) High-risk features of lupus nephritis: Importance of race and clinical and histological factors in 166 patients. Nephrol Dial Transplant 10:1620–1628PubMedGoogle Scholar
  124. 124.
    Casanova S, Mazzucco G, Barbiano di Belgiojoso G, Motta M, Boldorini R, Genderini A, Monga G (1995) Pattern of glomerular involvement in human immunodeficiency virus-infected patients: an Italian study. Am J Kidney Dis 26:446–453PubMedGoogle Scholar
  125. 125.
    Wang Y, Wang YP, Tay YC, Harris DC (2000) Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events. Kidney Int 58:1797–1804PubMedGoogle Scholar
  126. 126.
    Ma LJ, Fogo AB (2003) Model of robust induction of glomerulosclerosis in mice: importance of genetic background. Kidney Int 64:350–355PubMedGoogle Scholar
  127. 127.
    Qi Z, Fujita H, Jin J, Davis LS, Wang Y, Fogo AB, Breyer MD (2005) Characterization of susceptibility of inbred mouse strains to diabetic nephropathy. Diabetes 54:2628–2637PubMedGoogle Scholar
  128. 128.
    Yoshida H, Kuriyama S, Atsumi Y, Tomonari H, Mitarai T, Hamaguchi A, Kubo H, Kawaguchi Y, Kon V, Matsuoka K, Ichikawa I, Sakai O (1996) Angiotensin-I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus: risk for progression to chronic renal failure and mortality. Kidney Int 50:657–664PubMedGoogle Scholar
  129. 129.
    Marre M, Jeunemaitre X, Gallois Y, Rodier M, Chatellier G, Sert C, Dusselier L, Kahal Z, Chaillous L, Halimi S, Muller A, Sackmann H, Bauduceau B, Bled F, Passa P, Alhenc-Gelas F (1997) Contribution of genetic polymorphism in the renin–angiotensin system to the development of renal complications in insulin-dependent diabetes. J Clin Invest 99:1585–1595PubMedCrossRefGoogle Scholar
  130. 130.
    Brock JW 3rd, Hunley TE, Adams MC, Kon V (1998) Role of the renin–angiotensin system in disorders of the urinary tract. J Urol 160:1812–819PubMedGoogle Scholar
  131. 131.
    Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Bard JM, Bara L, Ricard S, Tiret L, Amoyel P, Alhenc-Gelas F, Soubrier F (1992) Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359:641–644PubMedGoogle Scholar
  132. 132.
    Yoshida H, Kon V, Ichikawa I (1996) Polymorphisms of the renin–angiotensin system genes in progressive renal diseases. Kidney Int 50:732–744PubMedGoogle Scholar
  133. 133.
    Boonstra A, de Zeeuw D, de Jong PE, Navis G (2001) Role of genetic variability in the renin–angiotensin system in diabetic and nondiabetic renal disease. Semin Nephrol 21:580–592PubMedGoogle Scholar
  134. 134.
    Hunley TE, Julian BA, Phillips JA 3rd, Summar ML, Yoshida H, Horn RG, Brown NJ, Fogo A, Ichikawa I, Kon V (1996) Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. Kidney Int 49:571–577PubMedGoogle Scholar
  135. 135.
    August P, Leventhal B, Suthanthiran M (2000) Hypertension-induced organ damage in African Americans: transforming growth factor-beta(1) excess as a mechanism for increased prevalence. Curr Hypertens Rep 2:184–191PubMedGoogle Scholar

Copyright information

© IPNA 2007

Authors and Affiliations

  1. 1.Department of PathologyVanderbilt University Medical CenterNashvilleUSA

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