Role of FXR/PPARγ pathway mediated fatty acid oxidation in acute kidney injury induced by cadmium in rats.

Cadmium is a common heavy metal pollutant in the environment. Kidney is the main target organ of cadmium toxicity, which can cause acute kidney injury. Fatty acid oxidation is the main source of energy produced by proximal renal tubular epithelial cells, and FXR is a bile acid receptor involved in lipogenesis. However, the regulatory mechanisms by which FXR on FAO remain unclear. In this study, both in vivo (SD rats) and in vitro (rPT cells) cadmium poisoning models were established to determine whether fatty acid oxidation is involved in cadmium-induced acute kidney injury. The results of in vivo experiments indicated that administration of 2.5 mg/kg Cd in rats induced acute kidney injury, characterized by a significant elevation in TG content and KIM-1 protein expression, as well as a marked reduction in the expression levels of fatty acid oxidation-related proteins, including CPT1A, PPAR γ, ATGL, SDHB, and FXR. Activation of FXR through its specific agonist significantly attenuated cadmium-induced renal damage. The in vitro results further revealed the effect of FXR on the abnormal FAO and lipid accumulation induced by cadmium. After FXR activation, the morphological damage of cells was significantly improved, the number of lipid droplets was significantly decreased, the expression of fatty acid oxidation related proteins was significantly increased, and the expression of Plin2 and KIM-1 proteins was significantly decreased. Next, to further explore the role of FXR/PPAR γ signaling in cadmium-induced lipid accumulation and FAO damage, we found that inhibited PPAR γ can significantly relieve cadmium induced rPT cells damage and lipid accumulation. In conclusion, regulation of fatty acid oxidation by FXR/PPAR γ pathway can effectively protect rats against acute kidney injury induced by cadmium.