Background

Prevalence of chronic kidney disease (CKD) is increasing along with the prevalence of obesity. Obesity is often associated with hyperinsulinemia, which in turn is linked with CKD. Rodent studies show that a high-fat diet induces hyperinsulinemia, accelerates renal lipogenesis as determined by the expressions of fatty acid synthase (Fasn) and Acetyl CoA Carboxylase (ACC), increases renal lipid accumulation and causes renal injury. We previously showed that transgenic expression of E4orf1 (E4), a virus-derived protein, directly improves glycemic control and reduces the endogenous insulin response to glucose load in mice. Using this model, we tested the hypothesis that “Improvement in glycemic control and hyperinsulinemia in E4 mice will be accompanied by a reduction in renal lipogenesis and lipid accumulation”.

Methods

About 29 wk old C57Bl/6J wild type (WT; n=8) or transgenic mice that expressed E4 in adipose tissue upon doxycycline (Dox) ingestion (E4; n=6) started chow diet with Dox for 6wk, followed by 10wk of a 60% high-fat diet (HFD) with Dox. As expected, E4 expression significantly improved glycemic control and reduced hyperinsulinemia as presented elsewhere. For this study, the expressions of Fasn and ACC and triglycerides (TG) accumulations were determined in the kidneys of these mice.

Results

Kidney weights normalized to total body weight did not differ between groups. Renal expressions of Fasn and ACC as determined by Western blots were significantly reduced in E4 group. The amount of TG normalized to kidney weight was significantly lower for the E4 group compared to WT (p=0.02).

Conclusions

E4 reduces lipogenesis and lipid accumulation in the kidneys, which may be linked to the improvement in hyperinsulinemia induced by E4. This is the first report of the role of E4 in influencing renal metabolism. Future studies should determine if the lowering of renal lipid accumulation by E4 protects from HFD-induced renal injury.US and International patents received for the use of E4.