Effects of Gemfibrozil on the Progression of Proteinuria in Obese Dahl Salt‐Sensitive Rats

Abstract

The prevalence of obesity has increased dramatically within the last decade and is now considered an independent risk factor for chronic kidney disease (CKD). Recently, we reported that obese Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant) rats exhibit dyslipidemia and renal injury independent of hyperglycemia that progresses to CKD. Interestingly, the kidneys from the SSLepRmutant strain displayed increased renal triglycerides and significant glomerular injury including podocyte foot process effacement and lipid droplets. Lipid‐lowering drugs such as fibrates have proven to be renoprotective in various models of kidney disease. Therefore, in the current study, we tested the effects of gemfibrozil, a fibrate, on the progression of renal injury in SSLepRmutant rats. Twelve‐week‐old SSWT and SSLepRmutant rats were separated into four groups (n=4 in each group): (1) SSWT and (2) SSLepRmutant rats treated with vehicle and (3) SSWT and (4) SSLepRmutant rats treated with gemfibrozil (200 mg/kg/day, orally, powdered food) for 4 weeks. Treatment with gemfibrozil had no effect on body weight or blood glucose levels in SSWT and SSLepRmutant rats. We observed greater than a 10‐fold increase in plasma triglyceride levels in the SSLepRmutant strain versus the values measured in SSWT rats (1265±380 and 117±19 mg/day, respectively). Gemfibrozil treatment significantly reduced plasma triglycerides by 64% in SSWT rats (41±20 mg/dL) and 57% in the SSLepRmutant strain (549±108 mg/dL). During the course of the study, proteinuria rose from 89±26 and 416±11 mg/day to 181±46 and 675±47 mg/day in SS and SSLepRmutant rats, respectively. Chronic treatment with gemfibrozil markedly decreased the progression of proteinuria by 52% in SSWT rats (87±17 mg/day) and 43% in the SSLepRmutant strain (385±75 mg/day). The kidneys from vehicle‐treated SSLepRmutant rats displayed significant glomerular injury with mesangial expansion and increased interstitial fibrosis and tubular protein casts compared to SSWT rats. Gemfibrozil treatment markedly decreased these renal abnormalities in both strains. These data indicate that reducing plasma lipid levels with gemfibrozil prevents the progression of proteinuria in both lean SSWT and obese SSLepRmutant rats.Support or Funding InformationThis study was supported by GM104357 and DK109133.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.