Obesity is closely linked with kidney disease. Chronic consumption of high-fat diets accelerates kidney inflammation and fibrosis. Our previous data show that diet-induced obesity (DIO) in mice increases plasma ET-1 levels, renal CD8+ T cell infiltration, and kidney interstitial fibrosis. While ET-1 and the subsequent signaling to ETA and ETB receptors has known pro-inflammatory and pro-fibrotic characteristics, the specific role in promoting DIO-related kidney disease remains unclear. We hypothesized that ET-1 signaling promotes renal inflammation and fibrosis in DIO. To test this, we placed male mice (C57BL/6J, 8-10 weeks old) on a normal diet (ND, 10% kcal fat) or high-fat diet (DIO, 45% kcal fat) ad libitum for 20 weeks. Starting at week 10, mice were assigned to Vehicle (Veh), selective ETA receptor antagonist atrasentan (Atr, 10mg/kg/day), or the dual ETA/B receptor antagonist bosentan (Bos, 100mg/kg/day) via the drinking water (n=4-6/group). Body weight was monitored, and renal inflammation and fibrosis were assessed by flow cytometry and histology. DIO mice gained significantly greater weight than ND group, and ET receptor antagonists did not affect body weight (NDVeh: 36. 3 ± 1. 40; DIOVeh: 49. 7 ± 0. 82; DIOAtr: 52. 1 ± 0. 63; DIOBos: 51. 5 ± 1. 02, p< 0. 0001). We quantified fibrosis and the number of renal CD3+ cells in the cortex and outer medulla by histology. Cortical fibrosis in DIO mice (% Picrosirius Red positive area) was significantly reduced by atrasentan (NDVeh: 0. 6 ± 0. 05; DIOVeh: 0. 9 ± 0. 05; DIOAtr: 0. 7 ± 0. 07; DIOBos: 0. 8 ± 0. 03, p=0. 004). In contrast, fibrosis in the vasa-recta associated area was significantly attenuated by bosentan (NDVeh: 1. 5 ± 0. 06, DIOVeh: 1. 9 ± 0. 2; DIOAtr: 1. 4 ± 0. 2; DIOBos: 1. 1 ± 0. 1, p=0. 02). The number of cortical CD3+ cells was not different among groups (p=0. 055). Interestingly, the DIOVeh group had a higher number of CD3+ cells in the vasa recta-associated area, and treatment with bosentan significantly attenuated the elevation (NDVeh: 2. 7±0. 3; DIOVeh: 4. 8±0. 3; DIOAtr: 4. 5±0. 5; DIOBos: 2. 4±0. 3, p=0. 0001). By flow cytometry, we assessed T cell populations and found that the number of renal CD8+ T cells was increased compared to ND, and both ET antagonists blunted this increase (CD8+ T cells, NDVeh: 9864±2154; DIOVeh: 29871±6844; DIOAtr: 17794±3166; DIOBos: 21107±1996, p=0. 03). Specific pro-migration and activation markers on CD8+ T cell populations were up-regulated with DIO and attenuated with both ET receptor antagonists (VLA4+, VCAM-1 ligand; NDVeh: 5745±1002, DIOVeh: 23053±5991, DIOAtr: 13299±2375, DIOBos: 14074±1633, p=0. 03 and PD1+, chronic activation marker; NDVeh: 3119±488, DIOVeh: 19025±5379, DIOAtr: 9928±2503, DIOBos: 10076±697, p=0. 02). Taken together, these data demonstrate that ET-1 signaling promotes renal inflammation and fibrosis in DIO, contributing to both migration and activation of renal CD8+ T cells with ETA receptors contributing to cortical fibrosis, while the ETB receptor contribute more to inflammation and fibrosis in the vasa recta-associated area of the kidney medulla. Funded by U2C/TL1 Deep South KUH PRIME U2C DK133422 & TL1 DK139566 from the NIH/NIDDK to TL, P01HL136267 to JSP and DMP. This abstract was presented at the American Physiology Summit 2026 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.
Luong et al. (Fri,) studied this question.