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

Poster Board Number: E97

Riyasat Ali (University of Houston), Sanket Patel (University of Houston), Tahir Hussain (University of Houston)

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.

This work is supported by the NIH grants R01 DK117495 and R01 DK61578