Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor β1,and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat

Abstract

Introduction

Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor β1 (TGF-β1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-β1 in diabetic rats.

Materials and methods

Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days.

Results

Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-β₁ increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-β1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558).

Conclusions

Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-β1.

Keywords

renin-angiotensin system TGF-β1 ACE-I ARB diabetes mellitus proteinuria

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References

Lewis EJ , Hunsicker LG , Bain RP , Rohde RD The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy . N Eng J Med 1993;329:1456-62.

Andersen S. , Tarnow L. , Rossing P. , Hansen BV , Parving HH Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int 2000;57:601-6.

Brenner BM , Cooper ME , de Zeeuv D. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type II diabetes and nephropathy. N Engl J Med 2001;345:861-9.

Anderson S. , Jung FF , Ingelfinger JR Renin-angiotensin system in diabetic rats: functional, immunochemical and molecular biologic correlations. Am J Physiol 1993;265:F477-F486.

Remuzzi A. , Perico N. , Amuchastegui CS et al. Short and long-term effect Oof angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol 1993;4:40-9.

Natif N. , Sclerovsky-Binjaminov F. , van Dijk DJ , Gafter U. , Boner G. , Erman A. Insulin and losartan reduce proteinuria and kidney hypertrophy in the pregnant diabetic rat. J Lab Clin Med 2003;142:167-72.

Jacobsen P. , Andersen S. , Jensen BR , Parving HH Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 2003;14:992-9.

Agarwal R. Add-on angiotensin receptor blockade with maximized ACE inhibition . Kidney Int 2002;59:2282-9.

Mogensen CE , Neldam S. , Tikkanen I. et al. Randomized 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 2000;321:1440-4.

10.

Noble NA , Border WA

Angiotensin II in renal fibrosis: Should TGFβ rather than blood pressure be the therapeutic target?

Sem Nephrol 1997 ;5:455-6.

11.

Ibrahim H. , Hostetter TH Aldosterone in renal disease. Curr Opinion Nephrol Hypertens 2003;12:159-64.

12.

Peters H. , Ritz E. Dosing angiotensin II blockers-beyond blood pressure. Nephrol Dial Transplant 1999;14:2568-70. 13. Yamamoto T. , Noble NA , Cohen AH et al. Expression of transforming growth factor β isoforms in human glomerular diseases. Kidney Int 1996;49:461-9.

13.

Hill C. , FlyvbjergA, Gronbaek H. et al.The renal expression of transforming growth factor β' isoforms and their receptors in acute and chronic experimental diabetes in rats. Endocrinol 2000;141:1196-208.

14.

Volpini RA , da Silva CG , Costa RS , Coimbra TM Effect of enalapril and losartan on the events that precede diabetic nephropathy in rats. Diabetes Metab Res Rev 2003;19:43-51.

15.

Agarwai R. , Siva S. , Dunn SR , Sharma K. Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-β levels. Am J Kid Dis 2002;39:486-92.

16.

Benigni A. , Zoja C. , Corna D. et al. Add-on anti-TGFβ' antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 2003;14:1816-24.

17.

Erman A. , van Dijk DJ , Chen-Gal B. et al. Angiotensin converting enzyme activity in the serum, lung and kidney of diabetic rats. Eur J Clin Invest 1993;23:615-20.

18.

Bradford MM A rapid and sensitive method for the quantitation of microgram quantity of protein utilizing of protein-dye binding. Anal Biochem 1976;72:248-54.

19.

Ots M. , Mackenzie HS , Troy JL , Rennke HG , Brenner BM 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 1998;9:224-30.

20.

Komine N. , Khang S. , Wead LM , Blanz RC , Gabbai FG Effect of combining an ACE inhibitor and an angiotensin II receptor blocker on plasma and kidney tissue angiotensin II levels. Am J Kid Dis 2002;39:159-64.

21.

Jacobsen P. , Andersen S. , Rossing K. , Jensen BR , Parving HH Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int 2003;63;1874-80.

22.

Rabkin R. , Shecter P. , Dong Shi J. , Boner G. Protein turnover in the hypertrophying kidney. Miner Electrol Metab 1996;22: 153-6.

23.

Leehey DJ , SinghAK , Alavi N. , Singa R. Role of angiotensin II in diabetic nephropathy. Kidney Int 2000;58(suppl 77):S93-S98.

24.

Wolf G. , Ziyadeh FN Renal tubular hypertrophy induced by angiotensin II. Sem Nephrol 1997;17:448-54.

25.

26.

Thurman JM , Schrier RW Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney. Am J Med 2003;114:588-98.

27.

Ruiz-Ortega M. , Gonzalez S. , Seron D. et al. ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in normotensive rat model of the immune complex nephritis. Kidney Int 1995;48:1778-91.

28.

Itoh Y. , Imamura S. , Yamamoto K. et al. Changes of endothelin in streptozotocin-induced diabetic rats: effects of an angiotensin converting enzyme inhibitor, enalapril maleate. J Endocrinol 2002;175:233-9.

29.

Navar LG , Harrison-Bernard LM , Nishiyama A. , Kobori H. Regulation of intrarenal angiotensin II in hypertension. Hypertension 2002;39[part 2]:316-22.

30.

van Dijk DJ , Boner G. , Erman A. Increased serum angiotensin-converting enzyme activity and plasma angiotensin II levels during pregnancy and postpartum in the diabetic rat. JRAAS 2002;2:193-8.

31.

Erman A. , Winkler J. , Chen-Gal B. et al. Inhibition of angiotensin converting enzyme by ramipril in serum and tissue of man.JHypertens 1991;9:1057-62.

32.

Cushman DW , Wang FL , Fung WC et al. Comparison in vivo, ex vivo and in vitro of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme. Br J Clin Pharmacol 1989;28:115S-131S.

33.

Goetz RM , Holtz J. Enhanced angiotensin-converting enzyme activity and impaired endothelium-dependent vasodilation in aortae from hypertensive rats: evidence for a causal link . Clin Sci 1999;97:165-74.

34.

van Dijk DJ , Erman A. , Erman T. , Chen- Gal B. , Sulkes J. , Boner G. Increased serum angiotensin converting enzyme activity in type I insulin-dependent diabetes mellitus: its relation to metabolic control and diabetic complications. Eur J Clin Invest 1994;24:463-7.

35.

Sharma K. , Eltayeb BO , McGowan TA et al. Captoprilinduced reduction of serum levels of transforming growth factor-β1 correlates with long-term renoprotection in insulindependent diabetic patients. Am J Kid Dis 1999;34:818-23.

36.

Obata J. , Nakamura T. , Kuroyanagi R. , Yosida Y. , Guo D. , Inagami T. Candesartan prevents the progression of glomerulosclerosis in genetic hypertensive rats. Kidney Int 1997; 63:S229-S231.