CD36-mediated podocyte lipotoxicity promotes foot process effacement

AbstractBackground Lipid metabolism disorders lead to lipotoxicity. The kidney is one of the most vulnerable organs in hyperlipidemia. The hyperlipidemia-induced early stage of renal injury mainly manifests as podocyte damage. CD36 mediates fatty acid uptake and the subsequent accumulation of toxic lipid metabolites, resulting in podocyte lipotoxicity. Methods Male Sprague-Dawley (SD) rats (20 rats) were divided into 2 groups: the normal control group (NC) and the high-fat diet group (HFD). Kidney tissue samples were collected for electron microscopy and Western blot analysis. Podocytes were cultured and treated with palmitic acid (PA) and sulfo-N-succinimidyl oleate (SSO). CD36 protein expression was measured by immunofluorescence and Western blot analysis. BODIPY (Boron-dipyrromethene) staining and Oil Red O staining was used to analyze fatty acid accumulation. Foot process damage was assessed by F-actin staining and electron microscopy. Results Podocyte foot process effacement and marked proteinuria occurred in the HFD group but not the NC group. CD36 protein expression was upregulated in the HFD group and in PA-treated podocytes (P < 0.05). PA-treated podocytes showed increased fatty acid accumulation, reactive oxygen species (ROS) production, and actin cytoskeleton rearrangement. However, pretreatment with the CD36 inhibitor SSO decreased lipid accumulation and ROS production and alleviated actin cytoskeleton rearrangement and foot process effacement in podocytes. Furthermore, the antioxidant N-acetylcysteine suppressed PA-induced podocyte foot process effacement and ROS generation. Conclusions CD36 participated in fatty acid–induced foot process effacement in podocytes via oxidative stress, and CD36 inhibitors may be helpful for early treatment of kidney injury.