Urotensin II receptor knockout mitigates high-fat diet-induced kidney injury

Chronic kidney disease is a debilitating complication of diabetes mellitus (DM). Urotensin II (UII) is a vasoactive hormone implicated in chronic kidney disease. UII levels in plasma and urine, as well as kidney tissue expression of UII and its receptor UT, are increased in diabetic kidney disease (DKD). However, the mechanisms that underlie UII-induced kidney injury in DM remain unresolved. In this study, we investigated the effects of UT gene deletion in mice subjected to high-fat diet-induced DKD. Experiments presented here used a global UT knockout (KO) mouse model. Wild-type (WT) and UT KO mice were fed either a high-fat diet (HFD, 60% fat) or a low-fat diet (LFD, 10% fat) for 33 weeks. WT HFD and KO HFD mice showed significant weight gain, hyperglycemia, and hyperinsulinemia. However, only WT HFD mice had albuminuria and elevated plasma CRELD2, an endoplasmic reticulum (ER) stress marker. Immunohistochemistry analysis of kidney slices showed increased global kidney and glomerular staining for collagen IV and fibronectin (markers of interstitial fibrosis) in WT HFD, which UT KO reversed. Pathological scoring of kidney tissue sections showed a significantly higher combined injury score (comprising inflammatory cell infiltrates, tubular casts, epithelial vacuolization, and mesangial expansion) in WT HFD than in KO HFD. WT HFD also showed podocyte foot process effacement and thickening of the glomerular basement membrane, indicators of glomerular filtration barrier dysfunction. UT KO protected HFD mice against glomerular injury. Similarly, immunofluorescence imaging of kidney slices showed increased global kidney and glomerular expression of tissue inhibitor of metalloproteinase 2 and insulin-like growth factor-binding protein 7, both biomarkers of kidney injury, in WT HFD which UT KO reversed. The levels of kidney injury biomarkers neutrophil gelatinase-associated lipocalin and Cystatin C were elevated in the plasma, and retinol-binding protein 4 and α1-microglobulin were elevated in the urine of WT HFD mice, with the effects reversed in KO HFD. These results show that HFD-induced albuminuria, ER stress, kidney injury, glomerular fibrosis, basement membrane thickening, and podocyte foot process effacement are diminished by UT gene deletion. Therefore, UT may be a promising therapeutic target for managing type 2 DKD. Dr. Adebiyi: NIH R01 HL151735 and R01 DK127625; APS 2020 John F. Perkins, Jr. Research Career Enhancement Award. Dr. Kanthakumar: AHA career development award (24CDA1273170). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.