N-methyl-D-aspartate receptor inhibition protects against obesity-induced kidney disease

Le résumé fourni par la source

BACKGROUND: Obesity-associated nephropathy is becoming increasingly prevalent, yet the molecular mechanisms linking metabolic stress to renal dysfunction remain unclear. N-methyl-D-aspartate receptors (NMDARs) are expressed in the kidney and are involved in the pathogenesis of different renal diseases. This study aimed to explore the role of NMDAR in obesity-induced kidney disease (OIKD). METHODS: NMDAR expression was assessed in a murine model of OIKD, an in vitro fat-overload model, and in kidney biopsies from chronic kidney disease (CKD) patients. We combined pharmacological inhibition with gain- and loss-of-function strategies: NMDAR antagonists, memantine and MK-801, were tested in vitro and in vivo, while NMDAR was overexpressed and downregulated in cultured proximal tubular epithelial (HK-2) cells to evaluate its contribution to OIKD. RESULTS: Free fatty acids (FFAs) exposure in HK-2 cells and high-fat diet (HFD) feeding in an OIKD mouse model led to increased GluN1, an essential subunit of NMDAR, accompanied by lipid accumulation and inflammatory responses associated with cellular injury. Kidney biopsies from CKD patients showed elevated GluN1 levels. In vitro, NMDAR antagonism attenuated FFA-induced cellular lipid accumulation and inflammation, regulated cellular redox homeostasis and suppressed FFA-induced p38 phosphorylation. GluN1 overexpression in HK-2 increased inflammatory markers, altered redox-regulating factors and promoted p38 activation. Treatment of cells with the p38 kinase inhibitor reduced FFA-induced GluN1 upregulation and attenuated inflammation. In vivo, NMDAR blockade reduced HFD-driven inflammation and tubular injury, and enhanced antioxidant gene expression. CONCLUSION: Our results demonstrate that renal NMDAR contributes to the pathogenesis of OIKD and underscore the therapeutic potential of targeting this receptor to attenuate inflammation and kidney injury in obesity-associated nephropathy.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.