Diet-Induced Obesity Leads to Increased Kidney Resident CD8+, but Not CD4+, T Cells in Male Mice Only

Obesity is a major risk factor for chronic kidney disease (CKD) in both sexes. Obese women tend to have a higher prevalence of CKD while obese men have higher rates of end-stage kidney disease. It is well-established that obesity alters tissue-resident T cells in adipose tissues, however little is known about this population in the kidney or if sex differences exist. We hypothesized that male diet-induced obese (DIO) mice have increased kidney resident T cells, while female DIO mice have no changes compared to same-sex mice on ND. Male and female C57BL/6J mice (8-12-week-old) were placed on either a chronic high-fat diet (DIO; 45% kcal fat, Research Diets D12451) or a normal diet (ND; 10% kcal fat, Research Diets D12450K) for 20 weeks. Male DIO mice have significantly greater body weight than male ND mice (DIO: 50.3 ± 0.6 g; ND: 33.8 ± 0.8 g; n=12; p<0.0001) whereas the amount of food intake of the two groups is similar (2.7 ± 0.06 g/day/mouse; n=12; p= 0.93). Female DIO mice also have significantly higher body weight than female ND mice (DIO: 42.0 ± 1.6 g; ND: 26.1 ± 1.0 g; n=6-7; p<0.0001) and both groups have similar food intake (2.3 ± 0.1 g/day/mouse; n=6-7; p=0.89). Kidney resident T cells were assessed by flow cytometry of surface markers, including CD69, CD103, and CD49a. Obese males exhibited a significant increase in the number of renal CD103+CD8+ T RM cells (DIO: 557.3 ± 75.6; ND: 243.0 ± 25.5; n=18; p=0.0004). No changes were observed in CD49a+CD8+ and CD69+CD8+ T cell subsets in male DIO and ND mice. Interestingly, DIO males showed no significant differences in the number of any subsets of renal CD4+T RM compared to ND, including CD69+CD4+ (p=0.66), CD103+CD4+ (p=0.42), and CD49a+CD4+ (p=0.16). DIO and ND females showed similar results in CD8+ T RM subsets, including CD103+CD8+ (p=0.22), CD49a+CD8+ (p=0.29), or CD69+CD8+ (p=0.49) T cells. Similar to males, DIO and ND females showed no differences in CD4+T RM , including CD69+CD4+ (p=0.26), CD103+CD4+ (p=0.14), and CD49a+CD4+ (p=0.91). Male DIO mice had significantly higher medullary interstitial fibrosis compared to male ND mice (Masson’s blue trichrome scoring with unbiased observer, 0=no fibrosis, 2=maximum fibrosis, DIO: 0.8 and ND: 0.1; n=10; p<0.0001). However, female DIO mice showed no increased interstitial fibrosis (p=0.15) compared to female ND mice. Endothelin-1 (ET-1) is a known mediator of immune cell activation and fibrosis. We found higher plasma ET-1 levels in male DIO mice compared to male ND mice (p=0.001), whereas female DIO and ND mice were similar (p=0.15). In summary, DIO leads to increased kidney CD8+ T RM cells but not CD4+ T RM , higher medullary interstitial fibrosis, and greater plasma ET-1 levels in male but not female mice. Tha Luong - U2C/TL1 Deep South KUH PRIME U2C DK133422 & TL1 DK139566 from the NIH/NIDDK David & Jennifer Pollock - R01 DK134562 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.