MPS 01-05 ACTIVATION OF RHO/RHO-KINASE PATHWAY IN PROXIMAL TUBULES AS A CULPRIT IN OBESITY-RELATED NEPHROPATHY

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Abstract

Objective:

A small GTP-binding protein, Rho, and its effector, Rho-kinase, have several pathological functions. We previously demonstrated that lipid accumulation and cellular hypertrophy activates Rho/ Rho-kinase through mechanical stretch in adipocytes, leading to inflammatory changes. We have also documented enlarged and vacuolated proximal tubules (PT) in obesity-related kidney damages. We examined whether Rho/Rho-kinase was activated in enlarged PT that were supposed to be under the mechanical stress and contributed to the pathophysiology of obesity-induced kidney damages.

Design and Method:

We created mice that overexpressed dominant negative RhoA genes specifically in PT under the control of promoter of sodium-phosphate co-transporter (PT-DN-RhoA) in C57BL/6J backgrounds. PT-DN-RhoA mice and their wild-type littermates (WT) were fed a high fat (HFD) or low fat diet (LFD) for 12 weeks.

Results:

WT on HFD developed obesity and manifested renal histological changes, including the enlargement and vacuolation of PT, the infiltration of inflammatory cells and the overexpression of stress fibers, which paralleled the increase in urinary excretion of albumin and NGAL of tubular injury markers. Enhanced Rho-kinase activity was noted particularly in PT.

Results:

PT-DN-RhoA mice exhibited not only the mitigation of tubular damages but also the amelioration of albuminuria and PT impairment.

Conclusions:

Excess fat intake causes obesity-induced renal injury, which are mediated by an activated Rho/Rho-kinase pathway in PT and inflammatory processes. It is surmised that hypertrophic process in PT during obesity formation affects Rho-kinase activation presumably through mechanical stress. This process subsequently induces inflammation and accelerates the histological changes of PT. The intervention of Rho/Rho-kinase may constitute a novel strategy blocking the progression of obesity-induced renal damages.

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