Urotensin II Receptor Deletion Mitigates Kidney Injury and Renal Lipid Remodeling in Mice Fed a Long-Term High-Fat Diet.

Urotensin II (UII) signaling through its Gq-coupled receptor (UT) has been implicated in metabolic and vascular dysfunction; however, its contribution to diabetic kidney disease (DKD) and renal lipid remodeling remains incompletely defined. We examined kidney injury and lipidomic alterations in wild-type (WT) and UT knockout (UT KO) mice fed a long-term high-fat diet (HFD). Male WT and UT KO mice were fed HFD (60% kcal fat) or low-fat diet (LFD; 10% kcal fat) for 33 weeks. Despite comparable HFD-induced obesity, hyperglycemia, and hyperinsulinemia, UT deletion significantly attenuated albuminuria, glomerular and tubular fibrosis, histopathologic injury scores, glomerular basement membrane thickening, and podocyte foot process effacement. UT deficiency also reduced systemic and renal markers of endoplasmic reticulum (ER) stress. Untargeted renal lipidomics profiling (1320 lipid species) revealed no genotype-dependent differences under LFD conditions. In contrast, HFD altered 52 lipid species in WT kidneys, prominently affecting phospholipids, glycosphingolipids, ceramides, sphingomyelins, and triglycerides. UT deletion mitigated dysregulation of 41 of these lipid species, indicating that UT signaling promotes maladaptive renal lipid remodeling in DKD. UT expression was confirmed in native and cultured mouse podocytes. In vitro, UII stimulated ER Ca2+ release, induced ER stress, and disrupted the actin cytoskeleton in podocytes; these effects were prevented by UT antagonism or inhibition of transient receptor potential canonical 6 channels. Collectively, these findings identify UII-UT signaling as a key mediator of lipid dysregulation and global kidney injury affecting the glomerular filtration barrier, tubules, and interstitium under HFD, supporting UT antagonism as a potential renometabolic therapeutic strategy.