Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice

Renisha Nadarajah, Rosangela Milagres, Marc Dilauro, Alex Gutsol, Fengxia Xiao, Joseph Zimpelmann, Chris Kennedy, Jan Wysocki, Daniel Batlle, Kevin D. Burns*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Angiotensin-converting enzyme 2 (ACE2) degrades angiotensin II to angiotensin-(1-7) and is expressed in podocytes. Here we overexpressed ACE2 in podocytes in experimental diabetic nephropathy using transgenic methods where a nephrin promoter drove the expression of human ACE2. Glomeruli from these mice had significantly increased mRNA, protein, and activity of ACE2 compared to wild-type mice. Male mice were treated with streptozotocin to induce diabetes. After 16 weeks, there was no significant difference in plasma glucose levels between wild-type and transgenic diabetic mice. Urinary albumin was significantly increased in wild-type diabetic mice at 4 weeks, whereas albuminuria in transgenic diabetic mice did not differ from wild-type nondiabetic mice. However, this effect was transient and by 16 weeks both transgenic and nontransgenic diabetic mice had similar rates of proteinuria. Compared to wild-type diabetic mice, transgenic diabetic mice had an attenuated increase in mesangial area, decreased glomerular area, and a blunted decrease in nephrin expression. Podocyte numbers decreased in wild-type diabetic mice at 16 weeks, but were unaffected in transgenic diabetic mice. At 8 weeks, kidney cortical expression of transforming growth factor-β1 was significantly inhibited in transgenic diabetic mice as compared to wild-type diabetic mice. Thus, the podocyte-specific overexpression of human ACE2 transiently attenuates the development of diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)292-303
Number of pages12
JournalKidney international
Volume82
Issue number3
DOIs
StatePublished - Aug 1 2012

Funding

We thank Mr A Carter for management of the mouse colonies. We thank Dr R Kothary (OHRI) and Mr Yves de Repentigny (OHRI) for performance of the mouse embryo injections. This study was supported by grants from the Canadian Institutes of Health Research (CIHR), and the Kidney Foundation of Canada (KFOC) to KDB and by NIDDK (grant 1R01DK080089-01A2) and JDRF grants to DB.

Keywords

  • ACE2
  • albuminuria
  • angiotensin
  • apoptosis
  • diabetes
  • podocyte

ASJC Scopus subject areas

  • Nephrology

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