ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice.
Angiotensin converting enzyme 2 (ACE2) is localized to the glomerular epithelial cells. Since ACE2 promotes the degradation of angiotensin II, a decrease in ACE2 activity could lead to the development of glomerular injury. We gave a specific ACE2 inhibitor, MLN-4760, for 4 weeks to mice rendered diabetic with streptozotocin. The urinary albumin/creatinine ratio was increased along with expansion of the glomerular matrix in diabetic mice treated with the inhibitor compared to the vehicle-treated mice. Glomerular staining of ACE was increased in the diabetic group and was further significantly increased in the diabetic group treated with MLN-4760. In renal vessels, ACE expression was also increased in the diabetic mice and, again, further increased in those diabetic mice treated with the ACE2 inhibitor. Our study shows that chronic pharmacologic ACE2 inhibition worsens glomerular injury in streptozotocin-induced diabetic mice in association with increased ACE expression.
Soler
M J
MJ
Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Wysocki
J
J
Ye
M
M
Lloveras
J
J
Kanwar
Y
Y
Batlle
D
D
D000804:Angiotensin II; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000473:pathology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D013311:Streptozocin; D015854:Up-Regulation / Q000235:genetics
C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D000804:Angiotensin II; D013311:Streptozocin; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine