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Kidney Week

Abstract: SA-PO601

Targeting IL-17 Activity Protects from Salt Sensitive Progression of CKD Following AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Mehrotra, Purvi, Indiana School of Medicine, Indianapolis, Indiana, United States
  • O'Shaughnessy, Riley P., IUSM, Indianapolis, Indiana, United States
  • Basile, David P., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Patients surviving AKI have a higher risk for chronic kidney disease (CKD). Previous studies in rats demonstrate that inhibition of T-cell activity (e.g., using mycophenolate or losartan) following recovery from AKI attenuates the subsequent development ofproteinuria, inflammation and fibrosis. Th17 cells, characterized by IL-17 secretion, are the predominant T helper subset associated with the AKI-to-CKD transition. Blockade of IL-17 activity using IL-17Rc receptor antagonist significantly decreased fibrosis and neutrophil recruitment in post ischemic rats compared to vehicle treated controls but other parameters of AKI-CKD transition have not been evaluated.

Methods

Male Sprague Dawley rats were subjected to unilateral I/R (40min) and allowed to recover for 5 weeks on low salt diet (0.4%). Rats were subjected contralateral nephrectomy UNx and elevated dietary NaCl (4%) for 4 additional weeks to hasten CKD. The rats were injected anti-IL-17 (5 mg/kg) or IgG control during the exposure to high salt diet and blood pressure measured by telemetry.

Results

Renal hypertrophy was evident in post-AKI IgG-treated rats relative to sham (~14%), which was significantly attenuated by IL-17 neutralizing antibody (p<0.05). There was a significant increase in the levels CD4+IL17+ cells and CD4+IFNγ+ cells in kidney of post AKI rats which was significantly reduced by IL-17 neutralizing antibody (IL17: IgG 17847±3787 and IL-17 7360±1680; p£0.05; IFNγ+: IgG 2703±495 and IL-17 1083±314; cells/g tissue p£0.05). Histological examination demonstrated that anti-IL17 antibody treatment reduced the level of renal fibrosis as indicated by picrosirius red staining. In addition, m-RNA expression of Kim-1 and Tgf-bwas reduced by 25% and 42% respectively. Mean arterial blood pressure was significantly attenuated by ~ 12 mm Hg in post-ischemic rats treated with anti-IL17 relative to vehicle treated post-AKI rats.

Conclusion

These data suggest that enhanced expression of CD4+IL-17 cells contribute to renal inflammation, fibrosis and hypertension in CKD following AKI.

Funding

  • NIDDK Support