Mehrotra, PurviUllah, Md MahbubCollett, Jason A.Myers, Sarah L.Dwinell, Melinda R.Geurts, Aron M.Basile, David P.2023-03-312023-03-312020-11-01Mehrotra P, Ullah MM, Collett JA, et al. Mutation of RORγT reveals a role for Th17 cells in both injury and recovery from renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2020;319(5):F796-F808. doi:10.1152/ajprenal.00187.2020https://hdl.handle.net/1805/32158To investigate T helper type 17 (Th17) cells in the setting of acute kidney injury, the gene encoding the master regulator of Th17 cell differentiation, that is, RAR-related orphan receptor-γ (RORγT), was mutated in Lewis rats using CRISPR/Cas9 technology. In response to 40 min of bilateral renal ischemia-reperfusion (I/R), RAR-related orphan receptor C (Rorc)-/- rats were resistant to injury relative to wild-type Rorc+/+ rats. This protection was associated with inhibition of IL-17 expression and reduced infiltration of CD4+ cells, CD8+ cells, B cells, and macrophages. To evaluate the effect of Th17 cells on repair, ischemia was increased to 50 min in Rorc-/- rats. This maneuver equalized the initial level of injury in Rorc-/- and Rorc+/+ rats 1 to 2 days post-I/R based on serum creatinine values. However, Rorc-/- rats, but not Rorc+/+ rats, failed to successfully recover renal function and had high mortality by 4 days post-I/R. Histological assessment of kidney tubules showed evidence of repair by day 4 post-I/R in Rorc+/+ rats but persistent necrosis and elevated cell proliferation in Rorc-/- rats. Adoptive transfer of CD4+ cells from the spleen of Rorc+/+ rats or supplementation of exogenous rIL-17 by an osmotic minipump improved renal function and survival of Rorc-/- rats following 50 min of I/R. This was associated with a relative decrease in the number of M1-type macrophages and a relative increase in the percentage of T regulatory cells. Taken together, these data suggest that Th17 cells have both a deleterious and a beneficial role in kidney injury and recovery, contributing to early postischemic injury and inflammation but also possibly being critical in the resolution of inflammation during kidney repair.en-USPublisher PolicyAcute kidney injuryCell proliferationInflammationLymphocytesArticle