Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism

Exposure of rats to elevated dietary salt following recovery from acute kidney injury (AKI) accelerates the transition to chronic kidney disease (CKD), and is dependent on lymphocyte activity. Here we tested whether high salt diet triggers lymphocyte activation in post-ischemic kidneys to worsen renal inflammation and fibrosis. Male Sprague- Dawley rats on a 0.4% salt diet were subjected to left unilateral ischemia-reperfusion and allowed to recover for 5 weeks. This resulted in a mild elevation of CD4(+) T-cells relative to sham animals. Contralateral unilateral nephrectomy and elevated dietary salt (4%) for 4 extra weeks hastened CKD and interstitial fibrosis. Activated T cells were increased in the kidney 3-fold after 4 weeks of elevated dietary salt exposure relative to post AKI rats prior to salt feeding. The T-cell subset was largely positive for IL-17, indicative of Th-17 cells. Because angiotensin II activity may influence lymphocyte activation, injured rats were given the AT1R antagonist, Losartan, along with high salt diet. This significantly reduced the number of renal Th-17 cells to levels of sham rats, and significantly reduced the salt-induced increase in fibrosis about half. In vitro studies in AKI-primed CD4(+) T cells indicated angiotensin II and extracellular sodium enhanced, and Losartan inhibited IL-17 expression. Thus, dietary salt modulates immune cell activity in post ischemic recovering kidneys due to the activity of local RAS suggesting participation of these cells in CKD progression post AKI.