Local Mineralocorticoid Receptor Activation and the Role of Rac1 in Obesity-Related Diabetic Kidney Disease

BACKGROUND/AIMS: Obesity and diabetes are intimately interrelated, and are independent risk factors for kidney disease. Overactivation of mineralocorticoid receptor (MR) is implicated in end organ damage of both pathologies. But the underlying mechanism of MR activation in kidney remains uncertain. We explored the involvement of Rac1, which we previously identified as a ligand-independent MR activator, in renal MR activation in vitro and in vivo. METHODS: We evaluated the MR activity and Rac1 activity under high-glucose stimulation using luciferase reporter system and glutathione S-transferase pull-down assay in cultured mesangial cells. To elucidate the role of Rac1 in vivo, we employed KKA(y), a mouse model of obesity-related type 2 diabetes, which spontaneously developed massive albuminuria and distinct glomerular lesions accompanied by increased plasma aldosterone concentration. RESULTS: High-glucose stimulation increased Rac1 activity and MR transcriptional activity in cultured mesangial cells. Overexpression of constitutively active Rac1 activated MR, and glucose-induced MR activation was suppressed by overexpression of dominant negative Rac1 or Rac inhibitor EHT1864. In KKA(y), renal Rac1 was activated, and nuclear MR was increased. EHT1864 treatment suppressed renal Rac1 and MR activity and mitigated renal pathology of KKA(y) without changing plasma aldosterone concentration. CONCLUSION: Our results suggest that MR activation plays an important role in the nephropathy of KKA(y) mice, and that glucose-induced Rac1 activation, in addition to hyperaldosteronemia, contributes to their renal MR activation. Along with MR blockade, Rac inhibition may potentially be a preferred option in the treatment of nephropathy in obesity-related diabetic patients.