Interleukin-17 mediates kidney endothelial dysfunction and contributes to diabetic kidney disease

Diabetes increases the risk of cardiovascular and diabetic kidney disease, in part, by increasing endothelial dysfunction. However, the precise molecular mechanisms are not well understood and pharmacological targets for microvascular dysfunction are unknown. Diabetes increases renal infiltration of immune cells homing the kidney and increases plasma interleukin 17 (IL17) levels in patients. In addition, IL17 has been associated to diabetes-induced end-organ damage. It’s not known whether IL17 directly induces signaling in endothelial cells (EC) of the renal vasculature and it’s role on endothelial dysfunction. We hypothesize that in a diabetic mouse model, there is an increase of kidney tissue resident immune cells that contribute to endothelial dysfunction through the release of interleukin 17. First, we isolated immune cells from kidneys of Akita mouse model of Type-1 diabetes and C57Bl6/J (control) and performed flow cytometry analysis. FACs results showed increased resident CD8/CD4+ and TH17+ lymphocytes in Akita, compared to age-matched C57 controls (n=6; p< 0.05), supporting a role of TH17 in diabetes. To determine if Akita mice exhibit arteriolar dysfunction, we measured endothelial-mediated vasodilation in microdissected and perfused afferent arterioles with attached glomeruli in vitro. In Akita diabetic mice (12-week-old), maximal dilation to Acetylcholine (Ach)10-5M was decreased by 65% (p< 0.025, n=7), indicating endothelial dysfunction. We then studied the direct effect of IL17 on endothelial cells of afferent arterioles. We found that IL17 (25 ng/ml), added to the lumen of perfused afferent arterioles, completely blocked Ach-induced vasodilation in Akita diabetic mice, whereas IL17 had no effect in Ach-induced vasodilation of control mice (n=7). Our data suggest that afferent arterioles of diabetic mice show enhanced IL17 signaling. To start dissecting the molecular signaling by IL17 in diabetes, we treated primary cultures of renal EC with IL17 for 24h in normal (NG: 5.5 mM) or high glucose (HG: 25 mM). After treatment with IL17 or vehicle, total RNA was extracted to perform bulk RNAseq. Over 12000 genes were statistically compared. In NG, IL17 induced 96 differentially expressed genes (DEGs, FDR p< 0.05). In contrast, in ECs on HG, IL17 induced 1205 DEGs (FDR p< 0.05 compared to HG alone). Bioinformatics analysis indicated upregulation of over 30 IL17 and IL10 signaling pathway genes, chemokines from the CXCL family, over 120 membrane trafficking genes and 31 circadian rhythm genes including Clock (Log2 fold 3.1±0.51, p< 10-5). We then tested whether inhibition of IL17 in the renal cortex of diabetic mice was protective. For this, we implanted subcapsular catheters in the renal cortex of Akita mice, connected to minipumps delivering IL17 neutralizing mAbs or vehicle (control) for 4 weeks. After 4-5 weeks, renal-specific IL17 inhibition decreased albuminuria (n=5, p< 0.05), urinary (pro)renin excretion, inflammatory genes of the IL17, TNF and TGFB pathway, and increased glomerular nephrin expression. Together our data indicate that IL17 induces signaling in renal EC that is increased in diabetic conditions supporting a differential pathological activation of this pathway in diabetes. We conclude that TH17 cells and IL17 contribute to diabetic kidney disease and glomerular damage progression. Understanding the contribution of the immune cells in the progression of diabetic kidney disease provide novel venues for pharmacological development. 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.