DEFICIENCY OF MINERALOCORTICOID SIGNALING IN MACROPHAGES PROVIDES PROTECTION AGAINST KIDNEY AND CARDIAC INJURY IN HYPERTENSIVE DIABETIC MICE.

G TESCH1,2, E OZOLS1, M YOUNG3, D NIKOLIC-PATERSON1,2
1Monash Health, Clayton, Australia, 2Monash University Centre for Inflammatory Diseases, Clayton, Australia, 3Hudson Institute of Medical Research, Clayton, Australia

Aim: To evaluate whether macrophage mineralocorticoid receptor signaling contributes to the development of kidney and cardiac disease in hypertensive diabetic mice.
Background: 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.
Methods: Transgenic mice with intact myeloid MR (MRflox/flox = WT) or myeloid MR deficiency (MRflox/flox LysMCre = MyMRKO) were developed on the hypertensive endothelial nitric oxide synthase deficient (Nos3-/-) mouse strain. Groups of these mice (n=13) were made diabetic with low dose streptozotocin (STZ) and were assessed after 15 weeks for the development of hypertension (systolic blood pressure), nephropathy (renal function impairment, albuminuria, renal injury) and cardiomyopathy (cardiac dysfunction–echocardiography).
Results: MR intact Nos3-/- mice with diabetes developed hypertension, albuminuria, renal function impairment (elevated cystatin-C), tubular injury (increased KIM-1 gene expression), and reduced cardiac function  (LV fractional shortening: diabetic 21% versus non-diabetic 31%), but no neutrophil infiltrate. In comparison, myeloid MR deficient Nos3-/- mice with similar diabetes had equivalent levels of hypertension, albuminuria and tubular injury, but showed improved renal function (plasma cystatin-C 48%↓, p<0.01) and improved cardiac function (LV fractional shortening  28%, p<0.01).
Conclusion: MR signaling in macrophages promotes injury in the diabetic kidneys and hearts of Nos3-/- mice without affecting hypertension. Therefore, MRAs can suppress diabetic nephropathy and diabetic cardiomyopathy by reducing macrophage-mediated injury independent of their ability to lower blood pressure.


Biography:
The research career of Greg Tesch has focused on the role of inflammation in diabetic nephropathy and other chronic kidney diseases.

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