Activation of the PPAR‐alpha Receptor Increases Proteinuria in Young Obese Dahl Salt‐Sensitive Rats

Abstract

Studies in the obese Dahl salt‐sensitive leptin receptor (SSLepRmutant) rats have shown that the progression of renal injury is associated with elevated plasma triglyceride levels and excessive renal lipid accumulation as early as 6 weeks of age. Previously, we observed that chronic treatment with gemfibrozil, an anti‐lipidemic drug via activation of PPAR‐α receptor, reduced plasma triglyceride levels, renal lipid accumulation, and renal fibrosis and improved renal function in old obese SSLepRmutant rats with chronic kidney disease (CKD). Since chronic treatment with gemfibrozil was effective in older animals and progressive proteinuria and renal injury occur prior to puberty in obese SSLepRmutant rats, the current study investigated the effects of gemfibrozil (200 mg/kg/day, orally) on the early progression of renal disease in young 4‐week old lean SS (n=6) and obese SSLepRmutant rats (n=6). Chronic treatment with gemfibrozil for 4 weeks significantly decreased plasma triglyceride levels by more than 50% in the young lean SS rats (115±18 vs. 47±13 mg/dL respectively), but only reduced these levels by 30% in young obese SSLepRmutant rats (417±99 vs. 287±127 mg/dL, respectively). Body weight and blood glucose levels were unaltered in both strains throughout the study. There were no significant differences in proteinuria between the obese SSLepRmutant and lean SS rats at baseline (27±9 vs. 4±1, respectively). However, proteinuria was significantly elevated in young obese SSLepRmutant rats compared to the values measured in young lean SS rats after 4 weeks (426±84 vs. 70±10 mg/day, respectively). While gemfibrozil treatment had no effect on protein excretion in older lean SS and obese SSLepRmutant rats, protein excretion was markedly increased in gemfibrozil‐treated young obese SSLepRmutant rats (722±114 mg/day). We did not observe any effect of gemfibrozil on protein excretion in young lean SS rats (82±21 mg/day). When examining glomerular injury (via PAS staining: % percentage of collapsed glomerular capillaries), chronic treatment with gemfibrozil had no effect on glomerular injury in these animals. Similar to the previous older animal study, young obese SSLepRmutant rats exhibited increased renal fibrosis (via Masson’s trichrome staining: % percentage of blue staining) when compared to the SS strain. Chronic treatment with gemfibrozil significantly reduced renal fibrosis in the young obese SSLepRmutant rats. Overall, these data may suggest that treatment with gemfibrozil in young obese SSLepRmutant rats increases the progression of proteinuria by reducing renal fibrosis indicating a potential side effect of gemfibrozil treatment in young animals. These data also indicate that additional experiments are needed to test the effects of gemfibrozil on renal hemodynamics, which may have an impact on the increased proteinuria observed in the young obese SSLepRmutant rats.Support or Funding InformationThis study was supported by GM104357 and DK109133.