Angiotensin AT2 Receptor Activation during Ischemic Injury Protects against High Salt‐Induced Hypertension and Proteinuria in the Long‐term: Role of IL‐17A Cells

Abstract

Short time renal ischemia/reperfusion (I/R) causes reversible acute kidney injury (AKI) that often recovers within 5‐7 days. However, a single event of AKI predisposes and makes kidneys susceptible to develop chronic kidney disease (CKD) in conditions such as obesity and hypertension. Recently we have shown that angiotensin type 2 receptor (AT2R) activation by the agonist compound C21 (C21) protects against I/R‐induced AKI in the early injury phase in terms of suppressing pro‐inflammatory cytokines and improving functional injury markers such as reducing proteinuria and blood urea nitrogen (BUN). The late recovery phase (day 5) in the I/R and I/R treated with C21 remained same i.e., the C21 treated and un‐treated animals fully recovered functionally to the same extent but with higher anti‐inflammatory IL‐10 producing and protective Treg cell (FoxP3+) in I/R+C21 compared I/R groups. However, the long‐term protective effect of the AT2R agonist C21 on these recovered kidneys against chronic injury is unknown. To address this question, male Sprague‐Dawley (SD) rats were administered C21 (0.3 mg/kg, i.p.) prior to 30‐minute bilateral renal ischemia and allowed to recover for 5 days, with daily C21 treatment (I/R+ C21), without treatment (I/R) and sham control. On 7th day, all the three groups were placed on high salt (1% NaCl) in drinking water for two weeks but without C21 treatment. On day 6 (prior to initiating high salt treatment), week 1 and 2 of the high salt treatment, renal function parameters (proteinuria), and T cells were quantitated in the blood and kidney (only at 2 weeks). On 6th day, all the three groups showed similar level of proteinuria, suggesting same renal function. However, at week 1 and 2, I/R group had significantly greater proteinuria, suggesting a function injury. Similarly, I/R group showed higher mean arterial blood pressure at two weeks compared with the I/R+C21 and sham control. Consistent to the higher proteinuria and blood pressure in I/R group, there were higher infiltrating proinflammatory (IL‐17A) cells in the kidney in I/R group compared with sham control and I/R+C21 groups. Also, kidney infiltrating CD45 cells, T cells and CD4 T cells were found to be similar among all the groups. Overall, the data indicate that I/R pre‐disposes the kidneys to high salt‐induced chronic injury which is completely prevented by AT2R agonist treatment during AKI phase. Moreover, AT2R’s protective effect could be related to preventing the T cell modulation into proinflammatory IL‐17A cells.