Activation of IL-17 Expressing Cells Following AKI Contributes to Sodium-Sensitive Hypertension, Development of Tertiary Lymphoid Structures, and Increased Angiotensin II (Ang II) Constriction

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Background: Following I/R induced AKI, rats develop salt-sensitive hypertension, CKD, and manifest enhanced vascular constriction sensitivity. Th17 (CD4+ IL17+) cells are induced following AKI and are restimulated by high salt diet. This study sought to determine the effects of IL17 on immune cell infiltration, hypertension and peripheral vascular reactivity post AKI. Methods: Study I: Male Sprague-Dawley rats were subjected to unilateral I/R (40min) and allowed to recover for 5 weeks on low salt diet (0.4%). Following a right nephrectomy (UNX), rats were provided elevated dietary salt (4%) and treated with either anti-IL17 (α-IL17) or non-immune IgG for 4 additional weeks. Study II: Additional studies were performed in wild type (WT) rats or rats with impaired Th17 activation (i.e., Rorc-/- ) to investigate microvascular responses to ANG II stimulation 5 weeks following unilateral I/R. Results: Renal hypertrophy was evident in post-AKI control IgG rats vs sham (~14%), and was significantly attenuated by αIL-17 (p<0.05). There was a significant increase in IL17+ cells, IFNγ+, total CD4 cells, CD8 cells, B-cells, neutrophils and dendritic/macrophages cells; all of which were attenuated by >50% in αIL-17 vs control IgG treated rats (p<0.05). Mean arterial pressure by telemetry was attenuated by α-IL17 treatment vs control IgG post I/R (131.0 ±1.2 vs 170.6± 11.6 mmHg; p<0.05). Histology showed substantial immune cell infiltration in post-AKI control rats, including apparent tertiary lymphoid structures (TLS), which were generally absent in αIL-17 treated rats (p<0.05). These structures contained loose aggregates of T and B cells and occasional evidence of B-geminal zones. In study II, alterations in vascular responses in isolated gracilis arterioles from WT rats 5 weeks post AKI showed enhanced pressor responses to ANG II versus sham. In contrast, this response was absent in vessels from Rorc-/- rats, which show impaired Th17 activity post-IR. Conclusion: These data suggest that the Th17/IL17 pathway has substantial effects on the pathophysiology of AKI-to-CKD, by influencing inflammation and the formation of TLS, as well as blood pressure control and peripheral vascular responses. Funding: NIDDK Support

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