Treatment With Gemfibrozil Prevents the Progression of Chronic Kidney Disease in Obese Dahl Salt-Sensitive Rats

Recently, we reported that Dahl salt-sensitive leptin receptor mutant (SS(LepR)mutant) rats exhibit dyslipidemia and renal lipid accumulation independent of hyperglycemia that progresses to chronic kidney disease (CKD). Therefore, in the current study, we examined the effects of gemfibrozil, a lipid-lowering drug (200 mg/kg/day, orally), on the progression of renal injury in SS and SS(LepR)mutant rats for 4 weeks starting at 12 weeks of age. Plasma triglyceride levels were markedly elevated in the SS(LepR)mutant strain compared to SS rats (1193 ± 243 and 98 ± 16 mg/day, respectively). Gemfibrozil treatment only reduced plasma triglycerides in the SS(LepR)mutant strain (410 ± 79 mg/dL). MAP was significantly higher in the SS(LepR)mutant strain vs. SS rats at the end of the study (198 ± 7 vs. 165 ± 7 mmHg, respectively). Administration of gemfibrozil only lowered MAP in SS(LepR)mutant rats (163 ± 8 mmHg). During the course of the study, proteinuria increased to 125 ± 22 mg/day in SS rats. However, proteinuria did not change in the SS(LepR)mutant strain and remained near baseline (693 ± 58 mg/day). Interestingly, treatment with gemfibrozil increased the progression of proteinuria by 77% in the SS(LepR)mutant strain without affecting proteinuria in SS rats. The renal injury in the SS(LepR)mutant strain progressed to CKD. Moreover, the kidneys from SS(LepR)mutant rats displayed significant glomerular injury with mesangial expansion and increased renal lipid accumulation and fibrosis compared to SS rats. Treatment with gemfibrozil significantly reduced glomerular injury and lipid accumulation and improved renal function. These data indicate that reducing plasma triglyceride levels with gemfibrozil inhibits hypertension and CKD associated with obesity in SS(LepR)mutant rats.