SUN-307 DEFICIENCY OF MINERALOCORTICOID RECEPTOR SIGNALING IN MACROPHAGES PROTECTS AGAINST KIDNEY AND CARDIAC INJURY IN HYPERTENSIVE DIABETIC MICE.

Introduction: Mineralocorticoid receptor antagonists (MRAs) reduce hypertension, inflammation and tissue injury in human and experimental diabetes. Furthermore, inflammation and injury in diabetic kidneys and hearts is dependent on infiltrating macrophages. Therefore, we hypothesized that the tissue protective effects of MRAs in diabetes is partially due to inhibition of MR signaling in macrophages. In this study, we used mice genetically deficient in myeloid MR to evaluate whether macrophage mineralocorticoid receptor signaling contributes to the development of kidney and cardiac disease in hypertensive diabetic mice. Method(s): Transgenic mice with intact myeloid MR (MRflox/flox) or myeloid MR deficiency (MRflox/flox LysMCre) were developed on the hypertensive endothelial nitric oxide synthase deficient (Nos3-/-) mouse strain. Groups of these mice (n=13) were made diabetic with multiple low dose injections of streptozotocin (STZ) and were assessed after 15 weeks for the development of hypertension (systolic blood pressure), nephropathy (albuminuria, renal function impairment and kidney damage) and cardiomyopathy (cardiac dysfunction-echocardiography and cardiac damage). Result(s): MR intact Nos3-/- mice with diabetes developed hypertension, kidney damage (macrophage accumulation, albuminuria, renal function impairment, hypertrophy, tubular injury, fibrosis), and cardiac damage (Left ventricular (LV) fractional shortening, macrophage accumulation, fibrosis), but no neutrophil infiltrate. In comparison, myeloid MR deficient Nos3-/- mice had equivalent diabetes, hypertension and albuminuria, but showed protection against loss of renal function (plasma cystatin-C reduced 48% vs MR intact mice with diabetes, p<0.01) and cardiac dysfunction (LV fractional shortening reduced 26% in MR intact mice with diabetes, p<0.01, but not in myeloid MR deficient mice with diabetes). The cardiac protection resulting from myeloid MR deficiency included the prevention of a diabetes-ind