Abstract 5080: Role of Mineralocorticoid Receptor/Rho/Rho-kinase Pathway in Obesity-Related Renal Injury
Both aldosterone and Rho-kinase are demonstrated independently to play an important role in renal injury and impaired insulin signalling. We therefore examined whether aldosterone/Rho/Rho-kinase pathway contributed to obesity-associated nephropathy. C57BL/6J mice were fed a high fat (HFD) or low fat diet (LFD) and mice on HFD were treated with a mineralocorticoid receptor (MR) antagonist, eplerenone. The mice on HFD developed obesity, and hyperglycemia compared with those on LFD, but manifested similar levels of systolic blood pressure. In HFD-fed mice, glomerular hypercellularity and increased mesangial matrix were noted (66.7±3.0 vs. 32.3±2.5 nuclei/gcs, p<0.01), which paralleled the increase in albuminuria (HFD, 0.13±0.04mg/gCr, P<0.01 vs LFD, 0.02±0.01mg/gCr). The treatment with eplerenone alleviated the histological changes and albuminuria (0.04±0.01mg/gCr, P<0.01 vs HFD) without alterations in systemic blood pressure. Adipose tissue weight and adipocyte size of HFD-fed mice were increased, which were ameliorated by eplerenone. Furthermore, enhanced Rho-kinase activity was noted in kidneys (2.0-fold, p<0.05) and adipose tissues (1.8-fold, p<0.05) from HFD-fed mice, as well as increased expressions of MCP-1, TNF-α and PDGF-B. All of these changes were attenuated by eplerenone. In HFD-fed mice, MR protein levels in the nuclear fraction were increased in kidneys (2.3-fold, p<0.05) and adipose tissues (2.0-fold, p<0.05) without elevation in serum aldosterone levels (LFD, 278±14mg/dl, HFD, 297±12mg/dl), and Sgk1, an effector of aldosterone, was upregulated (kidneys; 5.5-fold, p<0.01, adipose tissues; 2.2-fold, p<0.01). Finally, in mesangial cells, stimulation with aldosterone increased Rho-kinase activity, and pre-incubation with eplerenone prevented the aldosterone-induced activation of Rho-kinase. In conclusion, excess fat intake causes obesity and renal injury in C57BL/6J mice, and these changes are mediated by enhanced MR/Rho/Rho-kinase pathway and subsequent inflammatory process. Furthermore, both MR activation and the subsequent Rho-kinase stimulation are likely to participate in the development of obesity-associated nephropathy without elevation in serum aldosterone levels.