“Effects of Metformin on Attenuating Renal Dysfunction Through the Modulation of AMPK/PPARα Dependent Pathways in Obese Rats”

Abstract

Insulin signaling and lipid metabolism are disrupted in a condition of long‐term high‐fat diet (HF) consumption inducing insulin resistance, dyslipidemia and subsequent renal dysfunction as a consequence of the inactivation of AMP‐activated protein kinase (AMPK) and peroxisome proliferator‐activated receptor‐α (PPARα) pathway. We investigated the effects of metformin on renoprotective effect through the modulation of AMPK/PPARα dependent pathway in HF induced insulin resistant rats. Male Wistar rats were fed with HF for 16 weeks. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Insulin resistance, dyslipidemia, lipid accumulation and kidney injury were demonstrated in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were also exhibited in HF rats. Metformin could stimulate AMPK/PPARα pathway to regulate lipid metabolism. Moreover, renal inflammation markers, NF‐κB, COX2, iNOS expression, and renal fibrosis induced by HF were reduced in metformin treatment with the higher efficacy than gemfibrozil. Interestingly, renal Oat3 function and expression as well as kidney injury were improved in metformin and gemfibrozil treatment groups. Renal CD36 or SGLT2 expression were not different after treatment with metformin or gemfibrozil. In conclusion, metformin and gemfibrozil could restore the impairment of AMPK/PPARα signaling induced by HF to improve metabolic disturbance. Metformin demonstrated a greater efficacy than gemfibrozil in attenuating renal inflammation and fibrosis. The protective effects of metformin on renal injury induced by HF were involved in AMPK/PPARα dependent pathway.