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Pediatric Nephrology

, Volume 28, Issue 7, pp 1025–1036 | Cite as

An update on the pathomechanisms and future therapies of Alport syndrome

  • Damien Noone
  • Christoph LichtEmail author
Review

Abstract

Alport Syndrome (AS) is an inherited progressive disease that is caused by mutations of the genes encoding the key collagen chains, α3, α4, and α5, which are necessary for the composition of collagen type IV to form a robust glomerular basement membrane (GBM), capable of withstanding the significant biomechanical strain to which the glomerulus is subjected. Progressive loss of the filtration barrier allows excessive proteinuria, which ultimately leads to end-stage kidney disease (ESKD). The evidence for a beneficial renoprotective effect of renin-angiotensin-aldosterone system (RAAS) blockade by angiotensin-converting enzyme (ACE) inhibition and/or angiotensin receptor blockers (ARBs) is well established in AS and recent evidence has shown that it can significantly delay the time to onset of renal replacement therapy and ESKD. Future potential treatments of AS disease progression are evaluated in this review.

Keywords

Alport syndrome Proteinuria Glomerular basement membrane Proximal tubular epithelial cells Tubulointerstitium Inflammation Fibrosis 

Abbreviations

ACE

Angiotensin-converting enzyme

AP

Alternative pathway of complement activation

ARB

Angiotensin receptor I blocker

AS

Alport syndrome

BMP7

Bone morphogenetic protein 7

BMT

Bone marrow transplant

CCL2

Chemokine (C-C Motif) ligand 2 (MCP-1)

CCL5/RANTES

Chemokine (C-C Motif) ligand 5

CCR

β Chemokine receptor

CTGF

Connective tissue growth factor

CKD

Chronic kidney disease

CXCR

α Chemokine receptor

DDR

Discoidin domain receptor

DN

Diabetic nephropathy

ECM

Extracellular matrix

EGFR

Epidermal growth factor receptor

EMT

Epithelial-to-mesenchymal transformation

ERK

Extracellular regulated kinase

ESKD

End-stage kidney disease

GBM

Glomerular basement membrane

GFR

Glomerular filtration rate

HMG-CoA

3-Hydroxy-3-methylglutaryl CoA

MAC

Membrane attack complex

MCP-1

Monocyte chemotactic protein-1 (CCL-2)

MMP

Matrix metalloproteinase

MSC

Mesenchymal stromal cell

PPARγ

Peroxisome proliferator-activated receptor γ

PTEC

Proximal tubular epithelial cell

RAAS

Renin–angiotensin–aldosterone system

RANTES

Regulated upon activation, normal T-cell expressed, and secreted (CCL5)

TGF-β1

Transforming growth factor - β1

TNF-α

Tumor necrosis factor-α

XLAS

X-linked Alport syndrome

References

  1. 1.
    Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG (2003) Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med 348:2543–2556PubMedCrossRefGoogle Scholar
  2. 2.
    Thorner PS (2007) Alport syndrome and thin basement membrane nephropathy. Nephron Clin Pract 106:c82–c88PubMedCrossRefGoogle Scholar
  3. 3.
    Bekheirnia MR, Reed B, Gregory MC, McFann K, Shamshirsaz AA, Masoumi A, Schrier RW (2010) Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol 21:876–883PubMedCrossRefGoogle Scholar
  4. 4.
    Tryggvason K, Patrakka J, Wartiovaara J (2006) Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 354:1387–1401PubMedCrossRefGoogle Scholar
  5. 5.
    Van Agtmael T, Bruckner-Tuderman L (2010) Basement membranes and human disease. Cell Tissue Res 339:167–188PubMedCrossRefGoogle Scholar
  6. 6.
    Miglio G, Rosa AC, Rattazzi L, Grange C, Camussi G, Fantozzi R (2012) Protective effects of peroxisome proliferator-activated receptor agonists on human podocytes: proposed mechanisms of action. Br J Pharmacol. doi: 10.1111/j.1476-5381.2012.02026.x
  7. 7.
    Abrahamson DR, Hudson BG, Stroganova L, Borza DB, St John PL (2009) Cellular origins of type IV collagen networks in developing glomeruli. J Am Soc Nephrol 20:1471–1479PubMedCrossRefGoogle Scholar
  8. 8.
    Abrahamson DR, Isom K, Roach E, Stroganova L, Zelenchuk A, Miner JH, St John PL (2007) Laminin compensation in collagen alpha3(IV) knockout (Alport) glomeruli contributes to permeability defects. J Am Soc Nephrol 18:2465–2472PubMedCrossRefGoogle Scholar
  9. 9.
    Cosgrove D (2011) Glomerular pathology in Alport syndrome: a molecular perspective. Pediatr Nephrol 27:885–890PubMedCrossRefGoogle Scholar
  10. 10.
    Sayers R, Kalluri R, Rodgers KD, Shield CF, Meehan DT, Cosgrove D (1999) Role for transforming growth factor-beta1 in Alport renal disease progression. Kidney Int 56:1662–1673PubMedCrossRefGoogle Scholar
  11. 11.
    Zeisberg M, Khurana M, Rao VH, Cosgrove D, Rougier JP, Werner MC, Shield CF 3rd, Werb Z, Kalluri R (2006) Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease. PLoS Med 3:e100PubMedCrossRefGoogle Scholar
  12. 12.
    Rao VH, Meehan DT, Delimont D, Nakajima M, Wada T, Gratton MA, Cosgrove D (2006) Role for macrophage metalloelastase in glomerular basement membrane damage associated with Alport syndrome. Am J Pathol 169:32–46PubMedCrossRefGoogle Scholar
  13. 13.
    Rodgers KD, Rao V, Meehan DT, Fager N, Gotwals P, Ryan ST, Koteliansky V, Nemori R, Cosgrove D (2003) Monocytes may promote myofibroblast accumulation and apoptosis in Alport renal fibrosis. Kidney Int 63:1338–1355PubMedCrossRefGoogle Scholar
  14. 14.
    Rao VH, Lees GE, Kashtan CE, Nemori R, Singh RK, Meehan DT, Rodgers K, Berridge BR, Bhattacharya G, Cosgrove D (2003) Increased expression of MMP-2, MMP-9 (type IV collagenases/gelatinases), and MT1-MMP in canine X-linked Alport syndrome (XLAS). Kidney Int 63:1736–1748PubMedCrossRefGoogle Scholar
  15. 15.
    Rao VH, Lees GE, Kashtan CE, Delimont DC, Singh R, Meehan DT, Bhattacharya G, Berridge BR, Cosgrove D (2005) Dysregulation of renal MMP-3 and MMP-7 in canine X-linked Alport syndrome. Pediatr Nephrol 20:732–739PubMedCrossRefGoogle Scholar
  16. 16.
    Meehan DT, Delimont D, Cheung L, Zallocchi M, Sansom SC, Holzclaw JD, Rao V, Cosgrove D (2009) Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease. Kidney Int 76:968–976PubMedCrossRefGoogle Scholar
  17. 17.
    Vogel W, Gish GD, Alves F, Pawson T (1997) The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1:13–23PubMedCrossRefGoogle Scholar
  18. 18.
    Curat CA, Vogel WF (2002) Discoidin domain receptor 1 controls growth and adhesion of mesangial cells. J Am Soc Nephrol 13:2648–2656PubMedCrossRefGoogle Scholar
  19. 19.
    Gross O, Girgert R, Beirowski B, Kretzler M, Kang HG, Kruegel J, Miosge N, Busse AC, Segerer S, Vogel WF, Muller GA, Weber M (2010) Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease. Matrix Biol 29:346–356PubMedCrossRefGoogle Scholar
  20. 20.
    Barczyk M, Carracedo S, Gullberg D (2010) Integrins. Cell Tissue Res 339:269–280PubMedCrossRefGoogle Scholar
  21. 21.
    Girgert R, Martin M, Kruegel J, Miosge N, Temme J, Eckes B, Muller GA, Gross O (2010) Integrin alpha2-deficient mice provide insights into specific functions of collagen receptors in the kidney. Fibrogenesis Tissue Repair 3:19PubMedCrossRefGoogle Scholar
  22. 22.
    Borza CM, Su Y, Chen X, Yu L, Mont S, Chetyrkin S, Voziyan P, Hudson BG, Billings PC, Jo H, Bennett JS, Degrado WF, Eckes B, Zent R, Pozzi A (2012) Inhibition of integrin alpha2beta1 ameliorates glomerular injury. J Am Soc Nephrol 23:1027–1038PubMedCrossRefGoogle Scholar
  23. 23.
    Cosgrove D, Meehan DT, Grunkemeyer JA, Kornak JM, Sayers R, Hunter WJ, Samuelson GC (1996) Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev 10:2981–2992PubMedCrossRefGoogle Scholar
  24. 24.
    Hicks J, Mierau G, Wartchow E, Eldin K (2012) Renal diseases associated with hematuria in children and adolescents: a brief tutorial. Ultrastruct Pathol 36:1–18PubMedCrossRefGoogle Scholar
  25. 25.
    Ryu M, Migliorini A, Miosge N, Gross O, Shankland S, Brinkkoetter PT, Hagmann H, Romagnani P, Liapis H, Anders HJ (2012) Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury. J Pathol. doi: 10.1002/path.4046
  26. 26.
    Abbate M, Zoja C, Remuzzi G (2006) How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17:2974–2984PubMedCrossRefGoogle Scholar
  27. 27.
    Braun MC, Reins RY, Li TB, Hollmann TJ, Dutta R, Rick WA, Teng BB, Ke B (2004) Renal expression of the C3a receptor and functional responses of primary human proximal tubular epithelial cells. J Immunol 173:4190–4196PubMedGoogle Scholar
  28. 28.
    Tang S, Lai KN, Chan TM, Lan HY, Ho SK, Sacks SH (2001) Transferrin but not albumin mediates stimulation of complement C3 biosynthesis in human proximal tubular epithelial cells. Am J Kidney Dis 37:94–103PubMedCrossRefGoogle Scholar
  29. 29.
    Baines RJ, Brunskill NJ (2011) Tubular toxicity of proteinuria. Nat Rev Nephrol 7:177–180PubMedCrossRefGoogle Scholar
  30. 30.
    Chen J, Chen JK, Nagai K, Plieth D, Tan M, Lee TC, Threadgill DW, Neilson EG, Harris RC (2012) EGFR signaling promotes TGFbeta-dependent renal fibrosis. J Am Soc Nephrol 23:215–224PubMedCrossRefGoogle Scholar
  31. 31.
    Chiu FJ, Atkin CL (1983) Catabolites of the third component of complement in urines of hereditary nephritis patients. J Biol Chem 258:7200–7207PubMedGoogle Scholar
  32. 32.
    Abbate M, Zoja C, Rottoli D, Corna D, Perico N, Bertani T, Remuzzi G (1999) Antiproteinuric therapy while preventing the abnormal protein traffic in proximal tubule abrogates protein- and complement-dependent interstitial inflammation in experimental renal disease. J Am Soc Nephrol 10:804–813PubMedGoogle Scholar
  33. 33.
    Ichida S, Yuzawa Y, Okada H, Yoshioka K, Matsuo S (1994) Localization of the complement regulatory proteins in the normal human kidney. Kidney Int 46:89–96PubMedCrossRefGoogle Scholar
  34. 34.
    Biancone L, David S, Della Pietra V, Montrucchio G, Cambi V, Camussi G (1994) Alternative pathway activation of complement by cultured human proximal tubular epithelial cells. Kidney Int 45:451–460PubMedCrossRefGoogle Scholar
  35. 35.
    Clark EC, Nath KA, Hostetter MK, Hostetter TH (1990) Role of ammonia in tubulointerstitial injury. Miner Electrolyte Metab 16:315–321PubMedGoogle Scholar
  36. 36.
    Tang S, Zhou W, Sheerin NS, Vaughan RW, Sacks SH (1999) Contribution of renal secreted complement C3 to the circulating pool in humans. J Immunol 162:4336–4341PubMedGoogle Scholar
  37. 37.
    Tang S, Sheerin NS, Zhou W, Brown Z, Sacks SH (1999) Apical proteins stimulate complement synthesis by cultured human proximal tubular epithelial cells. J Am Soc Nephrol 10:69–76PubMedGoogle Scholar
  38. 38.
    Tang Z, Lu B, Hatch E, Sacks SH, Sheerin NS (2009) C3a mediates epithelial-to-mesenchymal transition in proteinuric nephropathy. J Am Soc Nephrol 20:593–603PubMedCrossRefGoogle Scholar
  39. 39.
    Rangan GK, Pippin JW, Couser WG (2004) C5b-9 regulates peritubular myofibroblast accumulation in experimental focal segmental glomerulosclerosis. Kidney Int 66:1838–1848PubMedCrossRefGoogle Scholar
  40. 40.
    Nangaku M, Pippin J, Couser WG (1999) Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J Am Soc Nephrol 10:2323–2331PubMedGoogle Scholar
  41. 41.
    Nangaku M, Pippin J, Couser WG (2002) C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys. J Am Soc Nephrol 13:928–936PubMedGoogle Scholar
  42. 42.
    Sayyed SG, Ryu M, Kulkarni OP, Schmid H, Lichtnekert J, Gruner S, Green L, Mattei P, Hartmann G, Anders HJ (2011) An orally active chemokine receptor CCR2 antagonist prevents glomerulosclerosis and renal failure in type 2 diabetes. Kidney Int 80:68–78PubMedCrossRefGoogle Scholar
  43. 43.
    Chung AC, Lan HY (2011) Chemokines in renal injury. J Am Soc Nephrol 22:802–809PubMedCrossRefGoogle Scholar
  44. 44.
    White RH, Raafat F, Milford DV, Komianou F, Moghal NE (2005) The Alport nephropathy: clinicopathological correlations. Pediatr Nephrol 20:897–903PubMedCrossRefGoogle Scholar
  45. 45.
    Churg J, Strauss L, Sherman RL (1974) Electron microscopic studies in hereditary nephritis. Birth Defects Orig Artic Ser 10:89–92PubMedGoogle Scholar
  46. 46.
    Spear GS (1974) The pathology of the kidney in the Alport syndrome. Birth Defects Orig Artic Ser 10:109–113PubMedGoogle Scholar
  47. 47.
    Ryu M, Kulkarni OP, Radomska E, Miosge N, Gross O, Anders HJ (2011) Bacterial CpG-DNA accelerates Alport glomerulosclerosis by inducing an M1 macrophage phenotype and tumor necrosis factor-alpha-mediated podocyte loss. Kidney Int 79:189–198PubMedCrossRefGoogle Scholar
  48. 48.
    Ninichuk V, Gross O, Reichel C, Khandoga A, Pawar RD, Ciubar R, Segerer S, Belemezova E, Radomska E, Luckow B, Perez de Lema G, Murphy PM, Gao JL, Henger A, Kretzler M, Horuk R, Weber M, Krombach F, Schlondorff D, Anders HJ (2005) Delayed chemokine receptor 1 blockade prolongs survival in collagen 4A3-deficient mice with Alport disease. J Am Soc Nephrol 16:977–985PubMedCrossRefGoogle Scholar
  49. 49.
    Clauss S, Gross O, Kulkarni O, Avila-Ferrufino A, Radomska E, Segerer S, Eulberg D, Klussmann S, Anders HJ (2009) Ccl2/Mcp-1 blockade reduces glomerular and interstitial macrophages but does not ameliorate renal pathology in collagen4A3-deficient mice with autosomal recessive Alport nephropathy. J Pathol 218:40–47PubMedCrossRefGoogle Scholar
  50. 50.
    Jedlicka J, Soleiman A, Draganovici D, Mandelbaum J, Ziegler U, Regele H, Wuthrich RP, Gross O, Anders HJ, Segerer S (2010) Interstitial inflammation in Alport syndrome. Hum Pathol 41:582–593PubMedCrossRefGoogle Scholar
  51. 51.
    Ryu M, Mulay SR, Miosge N, Gross O, Anders HJ (2011) Tumour necrosis factor-alpha drives Alport glomerulosclerosis in mice by promoting podocyte apoptosis. J Pathol 336:120–131Google Scholar
  52. 52.
    Cosgrove D, Rodgers K, Meehan D, Miller C, Bovard K, Gilroy A, Gardner H, Kotelianski V, Gotwals P, Amatucci A, Kalluri R (2000) Integrin alpha1beta1 and transforming growth factor-beta1 play distinct roles in Alport glomerular pathogenesis and serve as dual targets for metabolic therapy. Am J Pathol 157:1649–1659PubMedCrossRefGoogle Scholar
  53. 53.
    Nieto MA (2011) The ins and outs of the epithelial-to-mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 27:347–376PubMedCrossRefGoogle Scholar
  54. 54.
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedCrossRefGoogle Scholar
  55. 55.
    Cheng S, Lovett DH (2003) Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol 162:1937–1949PubMedCrossRefGoogle Scholar
  56. 56.
    Cheng S, Pollock AS, Mahimkar R, Olson JL, Lovett DH (2006) Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J 20:1898–1900PubMedCrossRefGoogle Scholar
  57. 57.
    Callis L, Vila A, Carrera M, Nieto J (1999) Long-term effects of cyclosporine A in Alport’s syndrome. Kidney Int 55:1051–1056PubMedCrossRefGoogle Scholar
  58. 58.
    Sigmundsson TS, Palsson R, Hardarson S, Edvardsson V (2006) Resolution of proteinuria in a patient with X-linked Alport syndrome treated with cyclosporine. Scand J Urol Nephrol 40:522–525PubMedCrossRefGoogle Scholar
  59. 59.
    Kashtan CE, Ding J, Gregory M, Gross O, Heidet L, Knebelmann B, Rheault M, Licht C (2012) Clinical practice recommendations for the treatment of Alport syndrome: a statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol. doi: 10.1007/s00467-012-2138-4
  60. 60.
    Webb NJ, Lam C, Shahinfar S, Strehlau J, Wells TG, Gleim GW, Le Bailly De Tilleghem C (2011) Efficacy and safety of losartan in children with Alport syndrome-results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial. Nephrol Dial Transplant 26:2521–2526PubMedCrossRefGoogle Scholar
  61. 61.
    Gross O, Licht C, Anders HJ, Hoppe B, Beck B, Tonshoff B, Hocker B, Wygoda S, Ehrich JH, Pape L, Konrad M, Rascher W, Dotsch J, Muller-Wiefel DE, Hoyer P, Knebelmann B, Pirson Y, Grunfeld JP, Niaudet P, Cochat P, Heidet L, Lebbah S, Torra R, Friede T, Lange K, Muller GA, Weber M (2012) Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int 81:494–501PubMedCrossRefGoogle Scholar
  62. 62.
    Ubaid-Girioli S, Ferreira-Melo SE, Souza LA, Nogueira EA, Yugar-Toledo JC, Coca A, Moreno H Jr (2007) Aldosterone escape with diuretic or angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy in patients with mild to moderate hypertension. J Clin Hypertens (Greenwich) 9:770–774Google Scholar
  63. 63.
    Sato A, Hayashi K, Naruse M, Saruta T (2003) Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 41:64–68PubMedCrossRefGoogle Scholar
  64. 64.
    Sato A, Hayashi K, Saruta T (2005) Antiproteinuric effects of mineralocorticoid receptor blockade in patients with chronic renal disease. Am J Hypertens 18:44–49PubMedCrossRefGoogle Scholar
  65. 65.
    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
  66. 66.
    Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ (2008) Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis 51:199–211PubMedCrossRefGoogle Scholar
  67. 67.
    Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF (2009) Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 4:542–551PubMedCrossRefGoogle Scholar
  68. 68.
    Kaito H, Nozu K, Iijima K, Nakanishi K, Yoshiya K, Kanda K, Przybyslaw Krol R, Yoshikawa N, Matsuo M (2006) The effect of aldosterone blockade in patients with Alport syndrome. Pediatr Nephrol 21:1824–1829PubMedCrossRefGoogle Scholar
  69. 69.
    Buck ML (2005) Clinical experience with spironolactone in pediatrics. Ann Pharmacother 39:823–828PubMedCrossRefGoogle Scholar
  70. 70.
    Ku E, Campese VM (2009) Role of aldosterone in the progression of chronic kidney disease and potential use of aldosterone blockade in children. Pediatr Nephrol 24:2301–2307PubMedCrossRefGoogle Scholar
  71. 71.
    Bensman A, Niaudet P (2010) Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr Nephrol 25:1197–1199PubMedCrossRefGoogle Scholar
  72. 72.
    Charbit M, Gubler MC, Dechaux M, Gagnadoux MF, Grunfeld JP, Niaudet P (2007) Cyclosporin therapy in patients with Alport syndrome. Pediatr Nephrol 22:57–63PubMedCrossRefGoogle Scholar
  73. 73.
    Massella L, Muda AO, Legato A, Di Zazzo G, Giannakakis K, Emma F (2010) Cyclosporine A treatment in patients with Alport syndrome: a single-center experience. Pediatr Nephrol 25:1269–1275PubMedCrossRefGoogle Scholar
  74. 74.
    Sheerin NS, Risley P, Abe K, Tang Z, Wong W, Lin T, Sacks SH (2008) Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury. FASEB J 22:1065–1072PubMedCrossRefGoogle Scholar
  75. 75.
    Abbate M, Zoja C, Corna D, Rottoli D, Zanchi C, Azzollini N, Tomasoni S, Berlingeri S, Noris M, Morigi M, Remuzzi G (2008) Complement-mediated dysfunction of glomerular filtration barrier accelerates progressive renal injury. J Am Soc Nephrol 19:1158–1167PubMedCrossRefGoogle Scholar
  76. 76.
    Saran AM, Yuan H, Takeuchi E, McLaughlin M, Salant DJ (2003) Complement mediates nephrin redistribution and actin dissociation in experimental membranous nephropathy. Kidney Int 64:2072–2078PubMedCrossRefGoogle Scholar
  77. 77.
    He C, Imai M, Song H, Quigg RJ, Tomlinson S (2005) Complement inhibitors targeted to the proximal tubule prevent injury in experimental nephrotic syndrome and demonstrate a key role for C5b-9. J Immunol 174:5750–5757PubMedGoogle Scholar
  78. 78.
    Morita Y, Ikeguchi H, Nakamura J, Hotta N, Yuzawa Y, Matsuo S (2000) Complement activation products in the urine from proteinuric patients. J Am Soc Nephrol 11:700–707PubMedGoogle Scholar
  79. 79.
    Piscione TD, Phan T, Rosenblum ND (2001) BMP7 controls collecting tubule cell proliferation and apoptosis via Smad1-dependent and -independent pathways. Am J Physiol Ren Physiol 280:F19–F33Google Scholar
  80. 80.
    Zeisberg M (2006) Bone morphogenic protein-7 and the kidney: current concepts and open questions. Nephrol Dial Transplant 21:568–573PubMedCrossRefGoogle Scholar
  81. 81.
    Almanzar MM, Frazier KS, Dube PH, Piqueras AI, Jones WK, Charette MF, Paredes AL (1998) Osteogenic protein-1 mRNA expression is selectively modulated after acute ischemic renal injury. J Am Soc Nephrol 9:1456–1463PubMedGoogle Scholar
  82. 82.
    Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S (2002) Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol 13(Suppl 1):S14–S21PubMedGoogle Scholar
  83. 83.
    Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968PubMedCrossRefGoogle Scholar
  84. 84.
    Mitu GM, Wang S, Hirschberg R (2007) BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury. Am J Physiol Ren Physiol 293:F1641–F1648CrossRefGoogle Scholar
  85. 85.
    Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R (2003) Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Ren Physiol 285:F1060–F1067Google Scholar
  86. 86.
    Tanaka M, Asada M, Higashi AY, Nakamura J, Oguchi A, Tomita M, Yamada S, Asada N, Takase M, Okuda T, Kawachi H, Economides AN, Robertson E, Takahashi S, Sakurai T, Goldschmeding R, Muso E, Fukatsu A, Kita T, Yanagita M (2010) Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. J Clin Invest 120:768–777PubMedCrossRefGoogle Scholar
  87. 87.
    Yanagita M (2006) Modulator of bone morphogenetic protein activity in the progression of kidney diseases. Kidney Int 70:989–993PubMedCrossRefGoogle Scholar
  88. 88.
    Lutz J, Yao Y, Song E, Antus B, Hamar P, Liu S, Heemann U (2005) Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats. Transplantation 79:655–661PubMedCrossRefGoogle Scholar
  89. 89.
    Naini AE, Harandi AA, Moghtaderi J, Bastani B, Amiran A (2007) Doxycycline: a pilot study to reduce diabetic proteinuria. Am J Nephrol 27:269–273PubMedCrossRefGoogle Scholar
  90. 90.
    Aggarwal HK, Jain D, Talapatra P, Yadav RK, Gupta T, Kathuria KL (2010) Evaluation of role of doxycycline (a matrix metalloproteinase inhibitor) on renal functions in patients of diabetic nephropathy. Ren Fail 32:941–946PubMedCrossRefGoogle Scholar
  91. 91.
    Guerrot D, Kerroch M, Placier S, Vandermeersch S, Trivin C, Mael-Ainin M, Chatziantoniou C, Dussaule JC (2011) Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy. Am J Pathol 179:83–91PubMedCrossRefGoogle Scholar
  92. 92.
    Yoshimura T, Matsuyama W, Kamohara H (2005) Discoidin domain receptor 1: a new class of receptor regulating leukocyte-collagen interaction. Immunol Res 31:219–230PubMedCrossRefGoogle Scholar
  93. 93.
    Flamant M, Placier S, Rodenas A, Curat CA, Vogel WF, Chatziantoniou C, Dussaule JC (2006) Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease. J Am Soc Nephrol 17:3374–3381PubMedCrossRefGoogle Scholar
  94. 94.
    Hachehouche LN, Chetoui N, Aoudjit F (2010) Implication of discoidin domain receptor 1 in T cell migration in three-dimensional collagen. Mol Immunol 47:1866–1869PubMedCrossRefGoogle Scholar
  95. 95.
    Ninichuk V, Gross O, Segerer S, Hoffmann R, Radomska E, Buchstaller A, Huss R, Akis N, Schlondorff D, Anders HJ (2006) Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice. Kidney Int 70:121–129PubMedCrossRefGoogle Scholar
  96. 96.
    Floege J, Kunter U, Weber M, Gross O (2006) Bone marrow transplantation rescues Alport mice. Nephrol Dial Transplant 21:2721–2723PubMedCrossRefGoogle Scholar
  97. 97.
    Sedrakyan S, Da Sacco S, Milanesi A, Shiri L, Petrosyan A, Varimezova R, Warburton D, Lemley KV, De Filippo RE, Perin L (2012) Injection of amniotic fluid stem cells delays progression of renal fibrosis. J Am Soc Nephrol. doi: 10.1007/s00467-012-2138-4O
  98. 98.
    Sugimoto H, Mundel TM, Sund M, Xie L, Cosgrove D, Kalluri R (2006) Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease. Proc Natl Acad Sci USA 103:7321–7326PubMedCrossRefGoogle Scholar
  99. 99.
    Prodromidi EI, Poulsom R, Jeffery R, Roufosse CA, Pollard PJ, Pusey CD, Cook HT (2006) Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome. Stem Cells 24:2448–2455PubMedCrossRefGoogle Scholar
  100. 100.
    Katayama K, Kawano M, Naito I, Ishikawa H, Sado Y, Asakawa N, Murata T, Oosugi K, Kiyohara M, Ishikawa E, Ito M, Nomura S (2008) Irradiation prolongs survival of Alport mice. J Am Soc Nephrol 19:1692–1700PubMedCrossRefGoogle Scholar
  101. 101.
    LeBleu V, Sugimoto H, Mundel TM, Gerami-Naini B, Finan E, Miller CA, Gattone VH 2nd, Lu L, Shield CF 3rd, Folkman J, Kalluri R (2009) Stem cell therapies benefit Alport syndrome. J Am Soc Nephrol 20:2359–2370PubMedCrossRefGoogle Scholar
  102. 102.
    Zhang C, Tan Y, Guo W, Li C, Ji S, Li X, Cai L (2009) Attenuation of diabetes-induced renal dysfunction by multiple exposures to low-dose radiation is associated with the suppression of systemic and renal inflammation. Am J Physiol Endocrinol Metab 297:E1366–E1377PubMedCrossRefGoogle Scholar
  103. 103.
    Wenzel RR, Littke T, Kuranoff S, Jurgens C, Bruck H, Ritz E, Philipp T, Mitchell A (2009) Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol 20:655–664PubMedCrossRefGoogle Scholar
  104. 104.
    Campese VM, Ku E, Bigazzi R, Bianchi S (2011) Do HMG-CoA reductase inhibitors improve kidney function? The saga continues. J Nephrol 24:550–553PubMedCrossRefGoogle Scholar
  105. 105.
    Gross O, Koepke ML, Beirowski B, Schulze-Lohoff E, Segerer S, Weber M (2005) Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688. Kidney Int 68:456–463PubMedCrossRefGoogle Scholar
  106. 106.
    Shroff R, Wan M, Rees L (2011) Can vitamin D slow down the progression of chronic kidney disease? Pediatr Nephrol. doi: 10.1007/s00467-011-2071-y
  107. 107.
    Gross O, Girgert R, Rubel D, Temme J, Theissen S, Muller GA (2011) Renal protective effects of aliskiren beyond its antihypertensive property in a mouse model of progressive fibrosis. Am J Hypertens 24:355–361PubMedCrossRefGoogle Scholar
  108. 108.
    Koepke ML, Weber M, Schulze-Lohoff E, Beirowski B, Segerer S, Gross O (2007) Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of progressive renal fibrosis in Alport syndrome. Nephrol Dial Transplant 22:1062–1069PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2012

Authors and Affiliations

  1. 1.Division of Nephrology, Department of PaediatricsThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Program in Cell BiologyThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of PaediatricsUniversity of TorontoTorontoCanada

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