Abstract 11898: KLF10 Deficiency in CD4+ T Cells Exacerbates Angiotensin II-Induced Perivascular Fibrosis

Introduction: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Angiotensin II (Ang II) contributes to vascular disease via promoting T-cell activation and end-organ damage. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. Objective: Kruppel-like Factor 10 is a transcription factor expressed in T cell subsets. We sought to investigate the role of KLF10 in CD4+ T cells in regulating vascular damage in an AngII mouse model. Methods: CD4-targeted KLF10 deficient (TKO) and CD4-Cre (WT) mice were generated and subjected to 28 days of Ang II infusion. Endpoint characterization included fibrotic organ transcriptomic analysis, multi-organ histology, flow cytometry, cytokine analysis, myograph vasoreactivity, and cardiac echocardiography. Results: TKO mice showed enhanced perivascular fibrosis compared to WT mice by histological analysis in the aorta, heart, and kidney. TKO mice had vessels with enhanced vasoconstriction to phenylephrine, hearts with impaired global longitudinal strain by echo, and kidneys with elevated albumin/creatinine ratio. However, no change was found in blood pressure between TKO and WT. Plasma IL-9 and IL-15 were increased in TKO mice. IL-9 mRNA and secreted protein were also increased in activated TKO CD4+ T cells, as well as in Ang II treated WT-CD4+ T cells in vitro . Mechanistic studies revealed that KLF10 regulated Il9 transcription through interaction with promoter region of Il9 by ChIP assay. Notably, injection of anti-IL9 antibody reversed perivascular fibrosis in Ang II infused TKO mice. Conclusion: CD4+ T cell deficiency of Klf10 exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9. Klf10 or IL-9 in T cells might represent novel therapeutic targets for the treatment of vascular or fibrotic diseases.