Distinct Role of the T cell ET-1/ETA Axis in Driving Diabetic Inflammation and Kidney Dysfunction in Male and Female Mice

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 ETA receptor. T cells express ETA and ETB receptors with similar levels of expression in males and females, yet the role of the T cell ET-1/ETA axis in driving sex differences in kidney inflammation and damage during type 1 diabetes (T1D) is unclear. We hypothesized that activation of the ET-1/ETA axis in T cells is pivotal in the development and progression of diabetic kidney disease, with a greater impact in males than females. Male and female mice without ETA receptor on T cells (T cell ETA KO) and floxed ETA controls were diabetic for 10wks (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 10wks of T1D. Flow cytometry studies on spleen, blood, and kidney assessed T cell phenotypic changes systemically and organ-specific. In response to T1D, male T cell ETA KO mice showed markedly lower protein excretion compared to controls (Floxed ETA vs. T cell ETA KO: 9.7±2 vs. 5.6±0.5 mg/day, n=4-8/group, p=0.0083). Diabetic floxed ETA controls showed a prominent decline in GFR, while diabetic T cell ETA KO mice sustained renal function (Baseline vs. 10 wks T1D: Floxed ETA: 324.1±18 vs. 236.9±17 uL/min/b.w., n=6-7/group, p=0.0034; T cell ETA KO: 318.0±20 vs. 295.9±21 uL/min/b.w., n=6/group, p=0.43). Lack of ETA receptor in males resulted in significant reduction of % positive and mean fluorescence intensity (MFI) values for TH memory cells (CD4+CD44+) and activated TH cells (CD4+CD69+), both in the spleen (memory and activation,% positive: p=0.032, p=0.04) and the kidney (% positive: p=0.034, p=0.031). While no genotypic differences in proteinuria were found in females, floxed females had elevated GFR after 10wks of T1D compared to KO females (Floxed ETA vs. T cell ETA KO: 305.4±48 vs. 164.1±49 uL/min/b.w., n=5/group, p=0.0010), suggesting that lack of ETA on T cells may protect females from reaching the hyperfiltration phase commonly preceding kidney failure. No genotype differences were found in the immune landscape in female spleen or kidney. Our findings demonstrate that activation of the T cell ET-1/ETA axis is critical for regulating T cell maturation, activation, and differentiation in diabetes, as well as for driving declining renal function during the early stages of diabetic kidney disease, but only in males. Thus, targeting the ET-1/ETA axis on T cells may represent a novel therapeutic approach to mitigating the progression of diabetic kidney disease, and may be useful in developing more sex-dependent drug targets against organ complications of diabetes. Funding: 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 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.