Fenofibrate Attenuates Renal Tubular Cell Apoptosis by Up-Regulating MCAD in Diabetic Kidney Disease

Abstract

Background Diabetic kidney disease (DKD) is a major diabetic microvascular complication. Fatty acid-induced lipotoxicity and apoptosis were associated with the exacerbation of DKD. However, the association of lipotoxicity with renal tubular apoptosis and the effects of fenofibrate on DKD are not fully understood. Methods Eight-week-old db/db mice were given fenofibrate or saline by gavage for 8 weeks. Human kidney proximal tubular epithelial (HK2) cells stimulated with palmitic acid (PA) and high glucose (HG) were used as a model of lipid metabolism disorders. Apoptosis was assessed with or without fenofibrate. The AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and AMPK inhibitor Compound C were used to determine the involvement of AMPK and Medium-chain acyl-CoA dehydrogenase (MCAD) in the regulation of lipid accumulation by fenofibrate. MCAD silencing was achieved by small interfering RNA (siRNA) transfection. Results Fenofibrate reduced triglyceride (TG) content and lipid accumulation in DKD. Importantly, renal function and tubular cell apoptosis were significantly improved by fenofibrate. Fenofibrate reduced apoptosis, accompanied by increased activation of the AMPK/FOXA2/MCAD pathway. MCAD silencing resulted in apoptosis and lipid accumulation despite fenofibrate treatment. Conclusion Fenofibrate improves lipid accumulation and apoptosis through the AMPK/FOXA2/MCAD pathway. MCAD may be a potential therapeutic target of DKD, and the use of fenofibrate as a treatment for DKD warrants further study.

Construction of a Nomogram-Based Prediction Model for the Risk of Diabetic Kidney Disease in T2DM

“…29 Our study found that TG was one of the predictors for DKD, consistent with the conclusion of previous studies. 30 The studies 31,34 found that at least eight standard predictors, such as eGFR, urinary albumin, SCR, T1DM disease course, HbA1c, age, and BMI, effectively indicated that Cys-C, renal resistance index, and renal injury molecular-1 may be related to the risk of DKD, which confirmed the potential value of Cys-C in predicting the risk of developing DKD in patients with T1DM. The results of this study showed that patients with higher Cys-C had a significantly increased risk of DKD, and subsequent analyses found that Cys-C could be used to predict the occurrence of DKD.…”

Lipid metabolism disorder in diabetic kidney disease

“…Fenofibrate decreased TG content and lipid accumulation in DKD and increased activation of the AMPK/FOXA2/medium-chain acyl-CoA dehydrogenase pathway, significantly reducing renal function and tubular cell apoptosis and slowing DKD progression ( 186 ).…”