Activation of the T Cell ET-1/ET_AAxis Drives Inflammation and Renal Damage During Type 1 Diabetes

Renal inflammation is a hallmark of diabetic kidney disease. Endothelin-1 (ET-1) is a potent vasoactive peptide that is critically implicated in diabetes and is elevated in patients with diabetic kidney injury and animal models. ET-1 is pro-inflammatory in the kidney via activation of its ET A receptor. T cells express ET A and ET B receptors, yet the role of the T cell ET-1/ET A axis in driving kidney inflammation and damage during type 1 diabetes (T1D) is unclear. We hypothesized that activation of the ET-1/ET A axis in T cells is pivotal in the development and progression of diabetic kidney disease. Male mice without ET A receptor on T cells (T cell ET A KO) and floxed ET A controls were diabetic for 10 weeks (streptozotocin, 50 mg/kg, i.p., 5 consecutive days). Urinary protein excretion and glomerular filtration rate (GFR) via FITC-sinistrin clearance were evaluated at baseline and after 10 weeks of T1D. Flow cytometry studies on spleen, blood, and kidney identified T cell phenotypic changes systemically and organ-specific. In response to T1D, T cell ET A KO mice showed markedly lower protein excretion compared to controls (Floxed ET A vs. T cell ET A KO: 9.66±2.4 vs. 5.57±0.48 mg/day, n=4-8/group, p=0.0083). Diabetic floxed ET A controls showed a prominent decline in GFR, while diabetic T cell ET A KO mice sustained renal function (Baseline vs. 10 wks T1D: Floxed ET A : 324.1±18 vs. 236.87±17 uL/min/b.w., n=6-7/group, p=0.0034; T cell ET A KO: 318.0±20 vs. 295.9±21 uL/min/b.w., n=6/group, p=0.43). % of CD4 + and CD8 + T cells were similar between groups, but we found distinct alterations in activation/differentiation markers in CD4 + and CD8 + T cell subtypes in kidney, spleen, and blood (by mean fluorescence intensity (MFI), n=3-6/group). Compared to diabetic floxed ET A controls, diabetic T cell ET A KO mice exhibited lower activation levels of kidney CD4 + T cells, as shown by lower MFI of CD44 (25612.3±2960 vs. 16172.5±2040, p=0.031) and CD69 (12018.0±597 vs. 7770.0±920, p=0.010). Similar trends were seen systemically, with lower splenic CD4 + CD44 + (p=0.009), CD8 + CD69 + (p=0.014), CD4 + RORγt + (p=0.046) and CD8 + RORγt + (p= 0.030) cells. The circulatory immune phenotype also showed decreased CD4 + T cell MFI of CD44 (p=0.0045) and CD69 (p=0.025), and lower CD8 + T cells MFI of CD44 (p=0.0091), CD69 (p=0.049), and RORγt (p=0.032). Our findings demonstrate that activation of the ET-1/ET A in T cells is critical for the decline of renal function and the development of T cell inflammation in the kidney during diabetes. In particular, we demonstrate that activation of the ET-1/ET A axis is key for regulating T cell maturation, activation, and differentiation in the diabetic setting. Thus, targeting the ET-1/ET A axis on T cells may represent a novel therapeutic approach to mitigating the progression of diabetic kidney disease. Deep South KUH PRIME U2C DK133422 & TL1 DK139566 to AJB and Diabetes Research Connection Funds to CDM 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.