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Mineralocorticoid Receptor Antagonist Reduces Renal Injury in Rodent Models of Types 1 and 2 Diabetes Mellitus

Division of Endocrinology, Diabetes, and Hypertension (C.G., D.M.-V., T.M.Y., E.M.O., T.K., N.L., L.P., G.H.W., V.R., G.K.A.), Department of Medicine, and Department of Pathology (G.P.M., M.F.T.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Gail K. Adler, M.D., Ph.D., Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: gadler{at}partners.org.

To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFß mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.

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