IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats

P Mehrotra, JA Collett, SD McKinney… - American Journal …, 2017 - journals.physiology.org
P Mehrotra, JA Collett, SD McKinney, J Stevens, CM Ivancic, DP Basile
American Journal of Physiology-Renal Physiology, 2017journals.physiology.org
T cells have been implicated in the pathogenesis of acute kidney injury (AKI) and its
progression to chronic kidney disease (CKD). Previous studies suggest that Th17 cells
participate during the AKI-to-CKD transition, and inhibition of T cell activity by
mycophenolate mofetil (MMF) or losartan attenuates the development of fibrosis following
AKI. We hypothesized that T cell-deficient rats may have reduced levels of IL-17 cytokine
leading to decreased fibrosis following AKI. Renal ischemis-reperfusion (I/R) was performed …
T cells have been implicated in the pathogenesis of acute kidney injury (AKI) and its progression to chronic kidney disease (CKD). Previous studies suggest that Th17 cells participate during the AKI-to-CKD transition, and inhibition of T cell activity by mycophenolate mofetil (MMF) or losartan attenuates the development of fibrosis following AKI. We hypothesized that T cell-deficient rats may have reduced levels of IL-17 cytokine leading to decreased fibrosis following AKI. Renal ischemis-reperfusion (I/R) was performed on T cell-deficient athymic rats (Foxn1rnu−/rnu−) and control euthymic rats (Foxn1rnu−/+), and CKD progression was hastened by unilateral nephrectomy at day 33 and subsequent exposure to 4.0% sodium diet. Renal fibrosis developed in euthymic rats and was reduced by MMF treatment. Athymic rats exhibited a similar degree of fibrosis, but this was unaffected by MMF treatment. FACS analysis demonstrated that the number of IL-17+ cells was similar between postischemic athymic vs. euthymic rats. The source of IL-17 production in euthymic rats was predominately from conventional T cells (CD3+/CD161). In the absence of conventional T cells in athymic rats, a compensatory pathway involving natural killer cells (CD3/CD161+) was the primary source of IL-17. Blockade of IL-17 activity using IL-17Rc receptor significantly decreased fibrosis and neutrophil recruitment in both euthymic and athymic rats compared with vehicle-treated controls. Taken together, these data suggest that IL-17 secretion participates in the pathogenesis of AKI-induced fibrosis possibly via the recruitment of neutrophils and that the source of IL-17 may be from either conventional T cells or NK cells.
American Physiological Society