Arginase-2 Mediates Diabetic Renal Injury

OBJECTIVE-To determine 1) whether renal arginase activity or expression is increased in diabetes and 2) whether arginase plays a role in development of diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS-The impact of arginase activity and expression on renal damage was evaluated in spontaneously diabetic Ins2(Akita) mice and in streptozotocin (STZ)-induced diabetic Dilute Brown Agouti (DBA) and arginase-2-deficient mice (Arg2(-/-)). RESULTS-Pharmacological blockade or genetic deficiency of arginase-2 conferred kidney protection in Ins2(Akita) mice or STZ-induced diabetic renal injury. Blocking arginases using S-(2-boronoethyl)-L-cysteine for 9 weeks in Ins2(Akita) mice or 6 weeks in STZ-induced diabetic DBA mice significantly attenuated albuminuria, the increase in blood urea nitrogen, histopathological changes, and kidney macrophage recruitment compared with vehicle-treated Ins2(Akita) mice. Furthermore, kidney arginase-2 expression increased in Ins2(Akita) mice compared with control. In contrast, arginase-1 expression was undetectable in kidneys under normal or diabetes conditions. Arg2(-/-) mice mimicked arginase blockade by reducing albuminuria after 6 and 18 weeks of STZ-induced diabetes. In wild-type mice, kidney arginase activity increased significantly after 6 and 18 weeks of STZ-induced diabetes but remained very low in STZ-diabetic Arg2(-/-) mice. The increase in kidney arginase activity was associated with a reduction in renal medullary blood flow in wild-type mice after 6 weeks of STZ-induced diabetes, an effect significantly attenuated in diabetic Arg2(-/-) mice. CONCLUSIONS-These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of DN. Diabetes 60:3015-3022, 2011