Journal Article

Effects and mechanisms of angiotensin II receptor blockade with telmisartan in a normotensive model of mesangioproliferative nephritis

Luigi Villa, Peter Boor, Andrzej Konieczny, Uta Kunter, Claudia R.C. van Roeyen, Bernd Denecke, Lin Gan, Michael B. Kupper, Kurt Hoffmann, Frank Eitner, Tammo Ostendorf and Jürgen Floege

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 26, issue 10, pages 3131-3143
Published in print October 2011 | ISSN: 0931-0509
Published online March 2011 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfr096
Effects and mechanisms of angiotensin II receptor blockade with telmisartan in a normotensive model of mesangioproliferative nephritis

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Background. Renoprotective actions of angiotensin receptor blockers are not well established in normotensive, low-grade proteinuric glomerular diseases. We examined the effect of low-dose telmisartan (LT) and high-dose telmisartan (HT) versus conventional antihypertensive therapy in the rat anti-Thy1.1 model of glomerulonephritis.

Methods. Rats were randomized on Day 4 after disease induction to no treatment (CT, control), LT or HT or hydrochlorothiazide + hydralazine (HCT + H).

Results. All rats remained normotensive: HT and HCT + H reduced blood pressure by 15–20%. LT, HT and HCT + H reduced glomerular endothelial cell proliferation and glomerular and interstitial matrix deposition on Day 14. Only HT reduced podocyte damage and tubular cell dedifferentiation on Day 9 and mesangial cell activation on Day 14. By gene expression analysis arrays, we identified discs-large homolog 1 and angiopoietin-like 4 as potential mediators of the HT effects. In addition, we identified several pathways possibly related to the pleiotropic effects of HT, including growth factor signalling, mammalian target of rapamycin signalling, protein ubiquitination, the Wnt-beta catenin pathway and hypoxia signaling.

Conclusions. In summary, treatment with HT, initiated after the induction of disease, ameliorates glomerular and tubulointerstitial damage. We provide the first comprehensive insight into the mechanisms underlying the renoprotective effect of high-dose angiotensin II receptor blockers (ARBs). Our study lays the basis for future investigations on novel pathways affected by ARBs in renal disease.

Keywords: Angptl-4; Dlgh1; fibrosis; mesangioproliferative glomerulonephritis; renin–angiotensin system blockade

Journal Article.  6192 words.  Illustrated.

Subjects: Nephrology

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