Angiotensin receptor blocker protection against podocyte-induced sclerosis is podocyte angiotensin II type 1 receptor-independent

Taiji Matsusaka, Takako Asano, Fumio Niimura, Masaru Kinomura, Akihiro Shimizu, Ayumi Shintani, Ira Pastan, Agnes B. Fogo, Iekuni Ichikawa

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

In the present study, we tested the hypothesis that the renoprotective effect of an angiotensin receptor blocker depends on the angiotensin II type 1 (AT1) receptor on podocytes. For this purpose, we generated podocyte-specific knockout mice for the AT1 gene (Agtr1a) and crossed with NEP25, in which selective podocyte injury can be induced by immunotoxin, anti-Tac(Fv)-PE38. Four weeks after the addition of anti-Tac(Fv)-PE38, urinary albumin:creatinine ratio was not attenuated in Agtr1a knockout/NEP25 mice (n=18) compared with that in control NEP25 mice (n=13; 8.08±2.41 in knockout versus 4.84±0.73 in control). Both strains of mice showed similar degrees of sclerosis (0.66±0.17 versus 0.82±0.27 on a 0 to 4 scale) and downregulation of nephrin (5.78±0.45 versus 5.65±0.58 on a 0 to 8 scale). In contrast, AT1 antagonist or an angiotensin I-converting enzyme inhibitor, but not hydralazine, remarkably attenuated proteinuria and sclerosis in NEP25 mice. Moreover, continuous angiotensin II infusion induced microalbuminuria similarly in both Agtr1a knockout and wild-type mice. Thus, angiotensin inhibition can protect podocytes and prevent the development of glomerulosclerosis independent of podocyte AT1. Possible mechanisms include inhibitory effects on AT1 of other cells or through mechanisms independent of AT1. Our study further demonstrates that measures that directly affect only nonpodocyte cells can have beneficial effects even when sclerosis is triggered by podocyte-specific injury.

Original languageEnglish
Pages (from-to)967-973
Number of pages7
JournalHypertension
Volume55
Issue number4
DOIs
Publication statusPublished - Apr 1 2010

Keywords

  • AT1 antagonist
  • Chronic renal failure
  • Glomerulosclerosis
  • Knockout mice
  • Podocyte
  • Proteinuria

ASJC Scopus subject areas

  • Internal Medicine

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