#2935 PHARMACOLOGICAL BLOCKADE OF NMDA RECEPTOR DECREASES KIDNEY INJURY INDUCED BY LIPOTOXICITY IN VITRO AND IN VIVO

Abstract

Abstract Background and Aims Obesity and hyperlipidemia are well established risks factors for kidney injury that can lead to chronic kidney disease (CKD). N-methyl-D-aspartate receptors (NMDARs) are expressed in the kidney and they are involved in the pathology of different renal diseases. The main objective of this study was to establish the role of the NMDAR in the lipotoxicity-induced kidney injury. Method In vivo, we used C57BL/6J mice fed a normal diet (ND) and high fat diet (HFD), as well as mice co-treated with HFD and NMDAR antagonists (HFD+memantine and HFD+MK-801). In vitro, we used renal proximal tubular epithelial cells (HK-2) treated with free fatty acids (FFAs) and a combination of FFAs and NMDAR antagonists. Lipid accumulation was analysed using Oil-Red staining. Expression of NMDAR1 and inflammation, fibrosis and oxidative stress markers were assessed by qPCR and western blot. Results After 10 weeks of diet, mice fed a HFD showed elevated levels of lipids in serum and kidney, compared with the ND. HFD induced an increase of expression of renal NMDAR mRNA and protein, as well as the expression of IL6, ICAM1, MCP1, TNFα and IL1β mRNA. Furthermore, HFD induced an increase of αSMA, vimentin, TGFβ1, fibronectin, OPN and NGAL levels in the kidney. Co-treatment with NMDAR antagonists significantly decreased levels of inflammatory markers, as well as the renal expression of αSMA, OPN and NGAL, but it did not have any effect on the hyperlipidemia induced by HFD. In vitro, treatment of HK-2 with different concentrations of FFAs induced accumulation of lipids in the cell, as well as the increase of the expression of NMDAR1 and markers of inflammation and oxidative stress. Co-treatment with NMDAR antagonists reversed changes induced by FFAs in HK-2 cells. The results were confirmed at the protein level. Conclusion Our results indicate that the NMDAR could be a new therapeutic target in the lipotoxicity-induced kidney injury.