What question did this study set out to answer?

The study aims to determine how the absence of ETA on dendritic cells affects immune response and kidney injury in obesity, with a focus on sex differences.

May 14, 2026

The Absence of ETA on Dendritic Cells Reduces Immune Activation and Protects Against Obesity-Induced Kidney Injury in Male, not Female, Mice

Key Points

The study aims to determine how the absence of ETA on dendritic cells affects immune response and kidney injury in obesity, with a focus on sex differences.
Utilized DC-specific ETA knockout (DC ETA KO) mice and floxed controls, with males (n = 3-5/group) and females (n = 5-8/group).
Mice were fed either a normal or high-fat diet for 25 weeks with assessments of metabolic function via glucose and insulin tolerance tests.
Renal injury was measured by urine protein levels and kidney T cell infiltration using immunohistochemistry.
Male DC ETA KO mice showed improved glucose tolerance (AUC: 42,026 ± 2,155 mg·min/dL vs. 60,310 ± 1,638 mg·min/dL, p = 0.0004) and insulin sensitivity (AUC: 17,957 ± 1,191 mg·min/dL vs. 24,177 ± 1,275 mg·min/dL, p = 0.0094).
Reduced CD3+ T cell infiltration in male DC ETA KO kidneys (0.331 ± 0.042 vs. 0.525 ± 0.060 %Threshold Area, p = 0.042), indicating lower immune activation.
Female DC ETA KO mice exhibited reduced proteinuria at early time points but not sustained at 25 weeks, highlighting sex differences.

Abstract

Endothelin-1 (ET-1) is a vasoactive peptide elevated in obesity that promotes inflammation and renal injury primarily through ETA receptors. Dendritic cells (DCs) link immune and metabolic pathways, but the contribution of DC-specific ET-1/ETA signaling to obesity-induced kidney damage and metabolic dysfunction remains unclear. We hypothesized that loss of ETA on DCs reduces immune activation and improves metabolic function in obesity, thereby protecting against obesity-induced kidney inflammation and damage. Given that sex differences are described in immune responses during obesity, we also hypothesized that males would exhibit greater protection than females. DC-specific ETA knockout (DC ETA KO) mice and floxed ETA controls (males: n = 3-5/group; females: n = 5-8/group) were fed a normal (NFD, 10% kcal) or high-fat diet (HFD, 45% kcal) for 25 weeks. Metabolic function was assessed by glucose and insulin tolerance tests. Renal injury was evaluated by urine protein levels. T cell infiltration in the kidney was detected by immunohistochemistry against CD3+ and quantified using Metamorph software. Physiological characteristics, including body composition (QMR), water intake, and urine output, were also evaluated. Male DC ETA KO mice fed HFD exhibited significantly improved glucose tolerance compared to floxed controls (AUC Floxed ETA vs. DC ETA KO: 60,310 ± 1,638 vs. 42,026 ± 2,155 mg·min/dL, p = 0.0004) and insulin sensitivity (AUC Floxed ETA vs. DC ETA KO: 24,177 ± 1,275 vs. 17,957 ± 1,191 mg·min/dL, p = 0.0094), indicating protection from diet-induced metabolic stress. Kidney CD3+ T cell infiltration was reduced in DC ETA KO mice (Floxed ETA vs. DC ETA KO: 0.525 ± 0.060 vs. 0.331 ± 0.042 %Threshold Area Positive CD3+, p = 0.042), consistent with lower immune cell activation. Female DC ETA KO mice showed reduced proteinuria at early time points (Floxed ETA vs. DC ETA KO: 0.363 ± 0.138 vs. 0.308 ± 0.093 mg/day, p = 0.041), although this effect was not sustained at 25 weeks. Body weight, fat mass, water intake, and urine output were similar in between sexes and not influenced by genotype. None of the groups developed hyperglycemia at any point of the study. Our findings demonstrate that loss of ETA signaling in DCs attenuates obesity-induced metabolic dysfunction and renal inflammation only in males, demonstrating a physiologically relevant role for DC-specific ET-1/ETA pathways in cardio-renal injury in this sex. These findings suggest DC ETA as a potential therapeutic target for obesity-associated kidney disease and highlight sex-dependent differences in immune and metabolic responses. Funding: UAB Presidential Honors Fellowship and R25 DK115353 in partnership with U54 DK126087 UAB Childhood Cystic Kidney Disease Core Center to EQR, Deep South KUH PRIME U2C DK133422 & TL1 DK139566 to AJB and U24 DK132740 LAUNCHED Pilot funding 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.

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