Electrolyte Blood Press.  2006 Mar;4(1):35-43. 10.5049/EBP.2006.4.1.35.

Renal Interstitial Fibrosis and Angiotensin Inhibition

• Koo JW

• KMID: 2052267
• DOI: http://doi.org/10.5049/EBP.2006.4.1.35

Abstract

Tubulointerstitial (TI) fibrosis is a final common pathway to progressive renal injury of all forms of renal disease. However, once renal damage reaches a certain threshold, progression of renal disease is consistent, irreversible, and largely independent of the initial injury. Angiotensin (AT) II is the main effector of the renin angiotensin system (RAS) and effects that may contribute to the onset and progression of renal damage. AT II may also directly contribute to accelerate renal damage by sustaining cell growth, inflammation, and fibrosis. Interventions that inhibit the activity of the RAS are renoprotective and may retard or even halt the progression of chronic nephropathies. Unilateral ureteral obstruction suggested as a well-established experimental model of progressive interstitial expansion and fibrosis. Although technically challenging, some investigators have successfully relieved the obstruction and reported significant reduction in interstitial fibrosis severity. Drugs that modulate the RAS, such as ACE inhibitors and angiotensin type 1 (AT1) receptor antagonists, have demonstrated protective renal effects and can ameliorate fibrosis. However, neither ACE inhibitor nor AT1 receptor blockade completely suppresses progression of renal disease. Dual blockade of the RAS with ACE inhibitors and AT1 receptor blockers may provide renal benefit beyond therapy with either drug alone, due to their potential additive beneficial effect.

MeSH Terms

Angiotensin-Converting Enzyme Inhibitors
Angiotensins*
Fibrosis*
Humans
Inflammation
Models, Theoretical
Renin-Angiotensin System
Research Personnel
Ureteral Obstruction
Angiotensin-Converting Enzyme Inhibitors
Angiotensins

Reference

1. Risdon RA, Sloper JC, de Wardener HE. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet. 1968; 2:363–366. PMID: 4173786.

2. Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis. 1992; 20:1–17. PMID: 1621674.

3. Strutz F. Novel aspects of renal fibrogenesis. Nephrol Dial Transplant. 1995; 10:1526–1532. PMID: 8559459.

4. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol. 2002; 283:F861–F875. PMID: 12372761.

5. Nabokov A, Waldherr R, Ritz E. Demonstration of the proliferation marker Ki-67 in renal biopsies : correlation to clinical findings. Am J Kidney Dis. 1997; 30:87–97. PMID: 9214406.

6. Markovic-Lipkovski J, Müller CA, Risler T, Muller GA. Association of glomerular and interstitial mononuclear leukocytes with different forms of glomerulonephritis. Nephrol Dial Transplant. 1990; 5:10–17. PMID: 2109281.

7. Hooke DH, Gee DC, Atkins RC. Leukocyte analysis using monoclonal antibodies in human glomerulonephritis. Kidney Int. 1987; 131:964–972. PMID: 3495689.

8. Remuzzi G, Perico N, Macia M, Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl. 2005; 99:S57–S65. PMID: 16336578.

9. Cochrane AL, Kett MM, Samuel CS, Campanale NV, Anderson WP, Hume DA, Little MH, Bertram JF, Ricardo SD. Renal structural and functional repair in a mouse model of reversal of ureteral obstruction. J Am Soc Nephrol. 2005; 16:3623–3630. PMID: 16221872.

10. Koo JW, Kim Y, Rozen S, Mauer M. Enalapril accelerates remodeling of the renal interstitium after release of unilateral ureteral obstruction in rats. J Nephrol. 2003; 16:203–209. PMID: 12774769.

11. Rastegar A, Kashgarian M. The clinical spectrum of tubulointerstitial nephritis. Kidney Int. 1998; 54:313–327. PMID: 9690198.

12. Wolgast MA, Larson M, Nygren K. Functional characteristics of renal interstitium. Am J Physiol Renal Fluid Electrolyte. 1981; 241:F105–F111.

13. Lemley KV, Kriz W. Anatomy of the renal interstitium. Kidney Int. 1991; 39:370–381. PMID: 2062030.

14. Liu Y. Renal fibrosis: New insights into the pathogenesis and therapeutics. Kidney Int. 2006; 69:213–217. PMID: 16408108.

15. Eddy AA. Can renal fibrosis be reversed? Pediatr Nephrol. 2005; 20:1369–1375. PMID: 15947978.

16. Kuncio GS, Neilson EG, Haverty T. Mechanisms of tubulointerstitial fibrosis. Kidney Int. 1991; 39:550–556. PMID: 2062038.

17. Nangaku M. Mechanisms of tubulointerstitial injury in the kidney : final common pathways to end-stage renal failure. Internal Medicine. 2004; 43:9–17. PMID: 14964574.

18. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med. 1998; 339:69–75. PMID: 9654536.

19. Nagle RB, Bugler RE. Unilateral obstructive nephropathy in the rabbit. II. Late morphologic changes. Lab Invest. 1978; 38:270–278. PMID: 633852.

20. Sharma AK, Mauer SM, Kim Y, Michael AF. Interstitial fibrosis in obstructive nephropathy. Kidney Int. 1993; 44:774–788. PMID: 8258955.

21. Pimentel JL, Sundell CL, WAT S, Kopp JB, Montero Á, Martínez-Maldonado M. Role of Angiotensin II in the expression and regulation of transforming growth factor-β in obstructive nephropathy. Kidney Int. 1995; 48:1233–1246. PMID: 8569085.

22. Klahr S. Obstructive nephropathy. Kidney Int. 1998; 54:286–300. PMID: 9648093.

23. Klahr S, Ishidoya S, Morrissey J. Role of Angiotensin II in the tubulointerstitial fibrosis of obstructive nephropathy. Am J Kidney Dis. 1995; 26:141–146. PMID: 7611245.

24. Chevalier RL, Kim A, Thornhill BA, Wolstenholme JT. Recovery following relief of unilateral ureteral obstruction in the neonatal rat. Kidney Int. 1999; 55:793–807. PMID: 10027917.

25. Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and Renal Fibrosis. Hypertension. 2001; 38:635–368. PMID: 11566946.

26. Johnson RJ, Alpers CE, Yoshimura A, Lombardi D, Pritzl P, Floege J, Schwartz SM. Renal injury from angiotensin II mediated hypertension. Hypertension. 1992; 19:464–474. PMID: 1568765.

27. Ruiz-Ortega M, Lorenzo O, Suzuki Y, Ruperez M, Egido J. Proinflammatory actions of angiotensin II. Curr Opin Nephrol Hypertens. 2001; 10:321–329. PMID: 11342793.

28. Wolf G, Neilson EG. Angiotensin II as a renal growth factor. J Am Soc Nephrol. 1993; 3:1531–1540. PMID: 8507808.

29. Gupta S, Clarkson MR, Duggan J, Brady HR. Connective tissue growth factor : potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney Int. 2000; 58:1389–1399. PMID: 11012874.

30. Brenner BM, Cooper ME, DeZeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345:861–869. PMID: 11565518.

31. Hilgers KF, Mann JFE. ACE inhibitors versus AT1 receptor antagonists in patients with chronic renal disease. J Am Soc Nephrol. 2002; 13:1100–1108. PMID: 11912272.

32. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Collaborative Study Group.Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345:851–860. PMID: 11565517.

33. Ruiz-Ortega M, Ruperez M, Esteban V, Egido J. Molecular mechanisms of angiotensin II-induced vascular injury. Curr Hypertens Rep. 2003; 5:737–739.

34. Erdos EG. Angiotensin I converting enzyme and the changes in our concepts through the years. Hypertension. 1990; 16:363–370. PMID: 2170273.

35. Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev. 2002; 1:621–636.

36. Wolf G, Butzmann U, Wenzel UO. The renin-angiotensin system and progression of renal disease : From hemodynamics to cell biology. Nephron Physiol. 2003; 93:3–13.

37. Esteban V, Lorenzo O, Rupéz M, Suzuki Y, Mezzano S, Blanco J, Kretzler M, Sugaya T, Egido J, Ruiz-Ortega M. Angiotensin II, via AT1 and AT2 Receptors and NF-κB Pathway, Regulates the Inflammatory Response in Unilateral Ureteral Obstruction. J Am Soc Nephrol. 2004; 15:1514–1529. PMID: 15153562.

38. Benigni A, Tomasoni S, Gagliardini E, et al. Blocking Angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis. J Am Soc Nephrol. 2001; 12:941–948. PMID: 11316852.

39. Ruggenenti P, Mosconi L, Vendramin G, Moriggi M, Remuzzi A, Sangalli F, Remuzzi G. ACE inhibition improves glomerular size selectivity in patients with idiopathic membranous nephropathy and persistent nephrotic syndrome. Am J Kidney Dis. 2000; 35:381–391. PMID: 10692263.

40. Remuzzi A, Perico N, Sanalli F, Vendramin G, Moriggi M, Ruggenenti P, Remuzzi G. ACE inhibition and AT II receptor blockade improve glomerular size-selectivity in IgA nephropathy. Am J Physiol Renal Physiol. 1999; 276:F457–F466.

41. Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, Maschio G, Brenner BM, Kamper A, Zucchelli P, Becker G, Himmelmann A, Bannister K, Landais P, Shahinfar S, de Jong PE, de Zeeuw D, Lau J, Levey AS. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A metaanalysis of patient-level data. Ann Intern Med. 2001; 135:73–87. PMID: 11453706.

42. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, Charleston J, Cheek D, Cleveland W, Douglas JG, Douglas M, Dowie D, Faulkner M, Gabriel A, Gassman J, Greene T, Hall Y, Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, Kusek J, Lash J, Lea J, Lewis JB, Lipkowitz M, Massry S, Middleton J, Miller ER 3rd, Norris K, O'Connor D, Ojo A, Phillips RA, Pogue V, Rahman M, Randall OS, Rostand S, Schulman G, Smith W, Thornley-Brown D, Tisher CC, Toto RD, Wright JT Jr, Xu S. African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis : a randomized controlled trial. JAMA. 2001; 285:2719–2728. PMID: 11386927.

43. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Marcantoni C, De Jong PE, De Zeeuw D, Shahinfar S, Ruggenenti P, Remuzzi G, Levey AS. AIPRD Study Group. Proteinuria as a modifiable risk factor for the progression of nondiabetic renal disease. Kidney Int. 2001; 60:1131–1140. PMID: 11532109.

44. Wolf G, Ritz E. Combination therapy with ACE inhibitors and Angiotensin II receptor blockers to halt progression of chronic renal disease : Pathophysiology and indications. Kidney Int. 2005; 67:799–812. PMID: 15698420.

45. Russo D, Minutolo R, Pisani A, Esposito R, Signoriello G, Andreucci M, Balletta MM. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis. 2001; 38:18–25. PMID: 11431176.

46. Ruilope LM, Aldigier JC, Ponticelli C, Esposito R, Signoriello G, Andreucci M, Balletta MM. European Group for the Investigation of Valsartan in Chronic Renal Disease. Safety of combination of valsartan and benazepril in patients with chronic kidney disease. J Hypertens. 2000; 18:89–95. PMID: 10678548.

47. Agarwal R. Add on Angiotensin receptor blockade with maximized ACE inhibition. Kidney Int. 2001; 59:2282–2289. PMID: 11380832.

48. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of Angiotensin II receptor blocker and Angiotensin-converting-enzyme inhibitor in nondiabetic renal disease (COOPERATE) : a randomized controlled trial. Lancet. 2003; 361:117–124. PMID: 12531578.

49. Koo JW, Ha IS. Effect of enalapril and losartan on the renal interstitium after release of unilateral ureteral obstruction UUO in rats. J Am Soc Nephrol. 2003; 14:589A. (abstract SU-PO 249).