Uncovering the pleiotropic effects of oleoylethanolamide on obesity-driven chronic kidney disease in mice

Metabolic alterations, resulting from obesity, drive chronic kidney disease (CKD) through mechanisms including lipotoxicity, inflammation, and fibrosis. Oleoylethanolamide (OEA), an endogenous compound belonging to the N-acylethanolamine family, has been widely studied for its metabolic properties. However, emerging evidence highlights its anti-inflammatory and anti-fibrotic effects. Here, we explored the effect of OEA on high-fat diet (HFD)-induced renal damage associated with obesity in mice. OEA treatment improved kidney function by restoring urine output and reducing proteinuria and albuminuria in obese mice. Moreover, OEA normalized serum creatinine and blood urea nitrogen levels, which were altered by HFD feeding, and decreased the transcription of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, associated with renal damage. OEA also counteracted renal glucose dysmetabolism by reducing glycogen content and modulating the protein expression of glucose transporters. Furthermore, OEA exerted marked anti-inflammatory and antifibrotic effects in kidney, further confirmed by a reduction in the transcription of pro-inflammatory and pro-fibrotic markers. OEA reduced renal steatosis, improving lipid metabolism through increased peroxisome proliferator-activated receptor-α and fibroblast growth factor 21 transcription and reduced triglyceride trafficking by the downregulation of diacylglycerol O-acyltransferase 1. Finally, to highlight the direct effect of OEA in the kidney, we confirmed its protective activity against lipotoxicity and demonstrated its ability to improve mitochondrial bioenergetics in human proximal tubular epithelial cells (HK-2). These results indicate that OEA may be a promising therapeutic molecule for restraining CKD-related alterations associated with obesity and metabolic disorders.