Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy

Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy Gavin Y. Oudit 1 , 2 , George C. Liu 3 , JiuChang Zhong 1 , 2 , Ratnadeep Basu 1 , 2 , Fung L. Chow 1 , 2 , Joyce Zhou 3 , Hans Loibner 4 , Evelyne Janzek 4 , Manfred Schuster 4 , Josef M. Penninger 5 , Andrew M. Herzenberg 6 , Zamaneh Kassiri 2 , 7 and James W. Scholey 3 1 Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; 2 Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; 3 Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 4 Apeiron Biologics, Vienna, Austria; 5 Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria; 6 Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada; 7 Department of Physiology, University of Alberta, Edmonton, Alberta, Canada. 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 ( Ins2 WT/C96Y ) and control C57BL/6J mice ( Ins2 WT/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 Ins2 WT/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 p47 phox 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 dia