Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy

  1. Gavin Y. Oudit1,2,
  2. George C. Liu3,
  3. JiuChang Zhong1,2,
  4. Ratnadeep Basu1,2,
  5. Fung L. Chow1,2,
  6. Joyce Zhou3,
  7. Hans Loibner4,
  8. Evelyne Janzek4,
  9. Manfred Schuster4,
  10. Josef M. Penninger5,
  11. Andrew M. Herzenberg6,
  12. Zamaneh Kassiri2,7 and
  13. James W. Scholey3
  1. 1Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada;
  2. 2Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada;
  3. 3Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada;
  4. 4Apeiron Biologics, Vienna, Austria;
  5. 5Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria;
  6. 6Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada;
  7. 7Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
  1. Corresponding author: Gavin Y. Oudit, gavin.oudit{at}ualberta.ca.

Abstract

OBJECTIVE Diabetic nephropathy is one of the most common causes of end-stage renal failure. Inhibition of ACE2 function accelerates diabetic kidney injury, whereas renal ACE2 is downregulated in diabetic nephropathy. We examined the ability of human recombinant ACE2 (hrACE2) to slow the progression of diabetic kidney injury.

RESEARCH DESIGN AND METHODS Male 12-week-old diabetic Akita mice (Ins2WT/C96Y) and control C57BL/6J mice (Ins2WT/WT) were injected daily with placebo or with rhACE2 (2 mg/kg, i.p.) for 4 weeks. Albumin excretion, gene expression, histomorphometry, NADPH oxidase activity, and peptide levels were examined. The effect of hrACE2 on high glucose and angiotensin II (ANG II)–induced changes was also examined in cultured mesangial cells.

RESULTS Treatment with hrACE2 increased plasma ACE2 activity, normalized blood pressure, and reduced the urinary albumin excretion in Akita Ins2WT/C96Y mice in association with a decreased glomerular mesangial matrix expansion and normalization of increased α-smooth muscle actin and collagen III expression. Human recombinant ACE2 increased ANG 1–7 levels, lowered ANG II levels, and reduced NADPH oxidase activity. mRNA levels for p47phox and NOX2 and protein levels for protein kinase Cα (PKCα) and PKCβ1 were also normalized by treatment with hrACE2. In vitro, hrACE2 attenuated both high glucose and ANG II–induced oxidative stress and NADPH oxidase activity.

CONCLUSIONS Treatment with hrACE2 attenuates diabetic kidney injury in the Akita mouse in association with a reduction in blood pressure and a decrease in NADPH oxidase activity. In vitro studies show that the protective effect of hrACE2 is due to reduction in ANG II and an increase in ANG 1–7 signaling.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received August 17, 2009.
    • Accepted October 31, 2009.
| Table of Contents