Involvement of glomerular renin−angiotensin system (RAS) activation in the development and progression of glomerular injury
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Recently, there has been a paradigm shift away from an emphasis on the role of the endocrine (circulating) renin−angiotensin system (RAS) in the regulation of the sodium and extracellular fluid balance, blood pressure, and the pathophysiology of hypertensive organ damage toward a focus on the role of tissue RAS found in many organs, including kidney. A tissue RAS implies that RAS components necessary for the production of angiotensin II (Ang II) reside within the tissue and its production is regulated within the tissue, independent of the circulating RAS. Locally produced Ang II plays a role in many physiological and pathophysiological processes such as hypertension, inflammation, oxidative stress, and tissue fibrosis. Both glomerular and tubular compartments of the kidney have the characteristics of a tissue RAS. The purpose of this article is to review the recent advances in tissue RAS research with a particular focus on the role of the glomerular RAS in the progression of renal disease.
KeywordsRenin−angiotensin system Angiotensin II TGF-β Tissue fibrosis Glomerulosclerosis
Since the discovery of kidney renin by Tigerstedt and Bergman , the renin−angiotensin system (RAS) has been established as an endocrine (circulating) system that plays a role in several organs to maintain the sodium and extracellular fluid balance, and thereby regulate blood pressure (BP). Angiotensin II (Ang II) is the most powerful biological product of this system and its action is transmitted by two main G-protein-coupled receptors with seven-transmembrane domains—Ang II type 1 receptor and type 2 receptor (AT1R and AT2R). Recently, the landscape of this system has become more complex with the discovery of new peptides, new proteins, new enzymatic pathways, new functions of RAS, and a tissue Ang II-generating system, a so-called ‘local’ or ‘tissue’ RAS, that acts at the tissue level in a paracrine and autocrine manner [2, 3]. A growing body of evidence from clinical and experimental studies has further highlighted the role that the tissue RAS plays in various disease conditions such as hypertension, inflammation, oxidative stress and tissue fibrosis in many organs [4, 5, 6, 7]. It is now well known that the kidney contains all of the elements of the RAS, and locally produced Ang II contributes to not only kidney ontogeny but also to the regulation of BP and progression of chronic kidney disease (CKD) [6, 7, 8]. The objective of this review is to explain the role of the renal tissue RAS, with particular focus on the role of the glomerular RAS in disease progression based on recent data. The presence and role of the tubular RAS in the kidney have been extensively reviewed by Kobori et al.  and will not be discussed here.
Recent advances in RAS biology
Ang II as a central mediator in progressive glomerular injury
Involvement of the glomerular RAS in disease progression
A growing body of evidence demonstrates that all of the components of the RAS are present within the glomerulus and the resultant product, Ang II, regulates glomerular capillary blood flow and capillary wall permeability, and contributes to the development and progression of glomerular diseases as described above. Seminal studies by Seikaly et al.  with micropuncture methods showed that the concentrations of total immunoreactive Ang (reflecting Ang II and lesser amounts of three fragments) in rat glomerular filtrate averaged 32 nM compared with 32 pM in systemic plasma, indicating that the Ang II concentration in Bowman’s space is 1000-fold higher than that in the systemic circulation. They subsequently demonstrated for the first time that isolated rat glomeruli can produce Ang II independent of neural innervation, vascular attachment, or exogenous influences. These findings firmly support the glomerulus-based synthesis of Ang II . Many studies using immunohistochemical and in situ hybridization techniques have reported that RAS components such as AGT, ACE, ACE2, Ang II, AT1R and AT2R can be detected in normal and diseased glomeruli in both rats and humans, and a parallel increase in AGT and Ang II, with inconsistent findings regarding the remaining RAS components, is seen in diseased glomeruli from several types of glomerulopathy in rats and humans [25, 26, 27, 28, 29, 30]. In genetically manipulated animals, rat glomeruli that have been modified with the human renin and AGT genes developed glomerular sclerosis and showed MC activation (α-smooth muscle actin-positive) . Upstream stimulatory factor 2 transgenic mice show increased renin expression and enhanced renin activity in the kidney, which stimulates the generation of glomerular Ang II which leads to glomerular hypertrophy and ECM accumulation accompanied by enhanced TGF-β expression and albuminuria . Furthermore, recent biochemical analyses of isolated glomeruli have revealed that, in diabetic rats, the level of glomerular Ang II peptide is increased due to an increased level of AGT protein and an increase in the formation of Ang II via an unidentified enzymatic pathway that does not involve ACE within glomeruli .
Glomerular Ang II production is also regulated by the expression ratio of ACE to ACE2 within the glomerulus . ACE2 plays a primary role in converting Ang II to Ang (1–7), which mediates vasodilation, antiproliferative, and antifibrotic actions via Mas receptor, and therefore has the potential to counterbalance the effects of ACEs . ACE2 is now considered to be an endogenous ACEI . In the diabetic mouse and human kidney, increased ACE expression and decreased ACE2 expression is observed in damaged glomeruli and indicates that the glomerular ACE/ACE2 balance plays a role in mediating glomerular injury, possibly by increasing the glomerular accumulation of Ang II [27, 42]. Notably, male ACE2 mutant (ACE2−/y) mice with an increase in the renal tissue Ang II level develop glomerulosclerosis . Sensitive indicators of ROS production, lipid peroxidation products and the glomerulosclerosis score were markedly enhanced in those mice while ARB prevented these increases, which strongly supports the notion that ACE2 plays a role in Ang II-induced glomerular injury. More recently, a similar relationship between ACE2 and ACE expression in diseased glomeruli was reported even in patients with IgAN .
New approach for the analysis of Ang peptides generated by the glomerular RAS pathway
Since RAS is a far more complex and dynamic system than was originally recognized, assays that are more selective, sensitive, and rapid than conventional radioimmunoassay and high-performance liquid chromatographic separation of peptide products are needed for the identification of RAS components and peptide-enzymatic cascades in RAS. The emergence of matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry (MS) allows us to clarify Ang metabolism with more specificity and ease than with previous methods. Recently, Velez et al. examined the metabolism of Ang I in freshly isolated intact rat glomeruli using MALDI-TOF-MS [10, 44, 45]. They showed that there is prominent glomerular conversion of Ang I–Ang (2–10) and Ang (1–7), mediated by AP-A and NEP, respectively, and suspected that the formation of these alternative Ang peptides may be critical for counterbalancing the local actions of Ang II within glomeruli. They then examined the contribution of POD or GEC to Ang metabolism in glomerulus using MALDI-TOF-MS in combination with cell culture methods [45, 46]. They demonstrated that POD expressed a functional intrinsic RAS characterized by AGT, NEP, AP-A, ACE2, and renin activities, which predominantly lead to Ang (1–7) and Ang (1–9) formation, as well as Ang II degradation . In contrast, GEC exhibited prominent ACE activity leading to Ang II, with the production of less Ang (1–7) and thus a lower degradative ability of Ang II , suggesting that injury to specific cell types in the glomeruli may lead to distinct effects on the glomerular RAS balance. In addition, many studies have reported that MC also express a functional intrinsic RAS characterized by AGT, prorenin, cathepsin B (a potential enzyme involved in renin activation), chymase, ACE, and ACE2, which primarily generates Ang II and very small amounts of Ang (1–7) and Ang (1–9) [45, 47, 48, 49]. Taken together, these findings suggest that variations in glomerular cell injury and the relative abundance of Ang I metabolites such as Ang II, Ang (1–7), Ang (1–9) and Ang (2–10) within glomeruli determine the net autocrine or paracrine effects of these Ang peptides on glomerular cells. A detailed analysis of the paramount enzymatic pathway in the RAS responsible for the conversion to these Ang peptides may provide therapeutic tools such as ACEIs for Ang II-mediated glomerular diseases.
Conclusion and future directions
There is no controversy regarding the concept that the glomerulus-based RAS plays a role in glomerular physiology and pathophysiology. Enhanced glomerular Ang II action in diseased glomeruli via ACE/Ang II/AT1R signaling promotes cell proliferation and ECM production, and decreases ECM degradation resulting in sclerotic lesions. Evidence in animal and human CKD has shown that RAS blockers such as ACEIs and ARBs are an effective and promising therapy for attenuating the progression of CKD beyond BP-lowering effect, which supports the above discussion. Several technical advances, including the use of molecular biology, peptide chemistry and the availability of transgenic and knock-out mice with altered expression of RAS components, have given us a more complex view of a glomerular RAS composed of a variety of peptidases, Ang peptides, and receptors involved in these Ang actions. The modulation of RAS pathways such as ACE2/Ang (1–7)/Mas receptor and PRR might become future therapeutic targets in CKD. Moreover, the identification of a glomerulus-specific enzymatic pathway for RAS activation could lead to a therapeutic strategy for attenuating the progression of glomerular disease in CKD.
SK is a recipient of a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan.
Conflict of interest
The author of this manuscript has no conflict of interest to disclose.
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