Human recombinant ACE2 reduces the progression of diabetic nephropathy.
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.


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 alpha-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 Calpha (PKCalpha) and PKCbeta1 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.
Oudit
Gavin Y
GY
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. gavin.oudit@ualberta.ca
Liu
George C
GC
Zhong
Jiuchang
J
Basu
Ratnadeep
R
Chow
Fung L
FL
Zhou
Joyce
J
Loibner
Hans
H
Janzek
Evelyne
E
Schuster
Manfred
M
Penninger
Josef M
JM
Herzenberg
Andrew M
AM
Kassiri
Zamaneh
Z
Scholey
James W
JW
D000199:Actins / Q000235:genetics; D000419:Albuminuria / Q000517:prevention & control; D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000235:genetics; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D006493:Heparin / Q000097:blood; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use
D000199:Actins; D001786:Blood Glucose; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000804:Angiotensin II; D006493:Heparin; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2