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Diabetologia
Published in: Diabetologia 11/2007

01-11-2007 | Article

Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats

Authors: D. J. Kelly, Y. Zhang, G. Moe, G. Naik, R. E. Gilbert

Published in: Diabetologia | Issue 11/2007

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Abstract

Aims/hypothesis

Blockade of the renin–angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of diabetic nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of diabetic nephropathy.

Methods

Using diabetic transgenic (mRen-2)27 rats, a rodent model of advanced diabetic nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg−1 day−1 by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg−1 day−1 in drinking water), over a 16 week period.

Results

Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in experimental diabetic nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril.

Conclusions/interpretation

These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in experimental diabetic nephropathy.
Literature
1.
Ritz E, Rychlik I, Locatelli F, Halimi S (1999) End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis 34:795–808CrossRef
2.
Bakris GL, Williams M, Dworkin L et al (2000) Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 36:646–661CrossRef
3.
Lewis EJ, Hunsicker LG, Clarke WR et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860CrossRef
4.
Brenner BM, Cooper ME, de Zeeuw D et al (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869CrossRef
5.
Nankervis A, Nicholls K, Kilmartin G, Allen P, Ratnaike S, Martin FI (1998) Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study. Metabolism 47:12–15CrossRef
6.
Cordonnier DJ, Pinel N, Barro C et al (1999) Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. J Am Soc Nephrol 10:1253–1263CrossRef
7.
Rossing K, Jacobsen P, Pietraszek L, Parving HH (2003) Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. Diabetes Care 26:2268–2274CrossRef
8.
Weinberg AJ, Zappe DH, Ashton M, Weinberg MS (2004) Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study. Am J Nephrol 24:340–345CrossRef
9.
Rossing K, Schjoedt KJ, Jensen BR, Boomsma F, Parving HH (2005) Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria. Kidney Int 68:1190–1198CrossRef
10.
Staessen JA, Li Y, Richart T (2006) Oral renin inhibitors. Lancet 368:1449–1456CrossRef
11.
Kelly DJ, Wilkinson-Berka JL, Allen TJ, Cooper ME, Skinner SL (1998) A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat. Kidney Int 54:343–352CrossRef
12.
Bunag RD (1973) Validation in awake rats of a tail-cuff method for measuring systolic pressure. J Appl Physiol 34:279–282CrossRef
13.
Kelly DJ, Hepper C, Zhang Y, Jaworski K, Wilkinson-Berka JL, Gilbert RE (2003) Protein kinase C β inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes 52:512–518CrossRef
14.
Lehr HA, Mankoff DA, Corwin D, Santeusanio G, Gown AM (1997) Application of Photoshop-based image analysis to quantification of hormone receptor expression in breast cancer. J Histochem Cytochem 45:1559–1565CrossRef
15.
Lehr HA, van der Loos CM, Teeling P, Gown AM (1999) Complete chromogen separation and analysis in double immunohistochemical stains using Photoshop-based image analysis. J Histochem Cytochem 47:119–126CrossRef
16.
Naik GO, Moe GW, Armstrong PW (2001) Specific and non-specific measurements of tissue angiotensin II cascade members. J Pharm Biomed Anal 24:947–955CrossRef
17.
Pilz B, Shagdarsuren E, Wellner M et al (2005) Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats. Hypertension 46:569–576CrossRef
18.
Mifsud SA, Skinner SL, Cooper ME, Kelly DJ, Wilkinson-Berka JL (2002) Effects of low-dose and early versus late perindopril treatment on the progression of severe diabetic nephropathy in (mREN-2)27 rats. J Am Soc Nephrol 13:684–692CrossRef
19.
Peterson JC, Adler S, Burkart JM et al (1995) Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 123:754–762CrossRef
20.
Parving HH, Andersen AR, Smidt UM, Svendsen PA (1983) Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1:1175–1179CrossRef
21.
Johnston CI, Risvanis J, Naitoh M, Tikkanen I (1998) Mechanism of progression of renal disease—current hemodynamic concepts. J Hypertens 16:S3–S7CrossRef
22.
Brenner BM (1983) Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 23:647–655CrossRef
23.
Anderson S (1997) Role of local and systemic angiotensin in diabetic renal disease. Kidney Int 52(63):S107–S110
24.
Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM (1986) Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 77:1925–1930CrossRef
25.
Anderson S, Rennke HG, Brenner BM (1986) Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 77:1993–2000CrossRef
26.
Gilbert RE, Cooper ME (1999) The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int 56:1627–1637CrossRef
27.
Bader R, Bader E, Grung KE, Markensen-Haen S, Christ H, Bohle A (1980) Structure and function of the kidney in diabetic glomerulosclerosis: correlations between morphological and functional parameters. Pathol Res Pract 167:204–216CrossRef
28.
Lane P, Steffes MW, Fioretto P, Mauer SM (1993) Renal interstitial expansion in insulin-dependent diabetes mellitus. Kidney Int 43:661–667CrossRef
29.
Gilbert RE, Cox A, Wu LL et al (1998) Expression of transforming growth factor-β1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of angiotensin converting enzyme inhibition. Diabetes 47:414–422CrossRef
30.
Kelly DJ, Gilbert RE, Cox AJ, Soulis T, Jerums GT, Cooper ME (2001) Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol 12:2098–2107CrossRef
31.
Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109:1417–1427CrossRef
32.
Nguyen G (2006) Increased cyclooxygenase-2, hyperfiltration, glomerulosclerosis, and diabetic nephropathy: put the blame on the (pro)renin receptor? Kidney Int 70:618–620CrossRef
33.
Mullins JJ, Peters J, Ganten D (1990) Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 344:541–544CrossRef
34.
Peters J, Munter K, Bader M, Hackenthal E, Mullins JJ, Ganten D (1993) Increased adrenal renin in transgenic hypertensive rats, TGR(mREN2)27, and its regulation by cAMP, angiotensin II, and calcium. J Clin Invest 91:742–747CrossRef
35.
Campbell DJ, Rong P, Kladis A, Rees B, Ganten D, Skinner SL (1995) Angiotensin and bradykinin peptides in the TGR(mRen-2)27 rat. Hypertension 25:1014–1020CrossRef
36.
Campbell DJ, Kelly DJ, Wilkinson-Berka JL, Cooper ME, Skinner SL (1999) Increased bradykinin and “normal” angiotensin peptide levels in diabetic Sprague–Dawley and transgenic (mRen-2)27 rats. Kidney Int 56:211–221CrossRef
37.
Xue C, Siragy HM (2005) Local renal aldosterone system and its regulation by salt, diabetes, and angiotensin II type 1 receptor. Hypertension 46:584–590CrossRef
Metadata
Title
Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats
Authors
D. J. Kelly
Y. Zhang
G. Moe
G. Naik
R. E. Gilbert
Publication date
01-11-2007
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 11/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-007-0795-9

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