Faculty Collaboration Database

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 Nov 01;319(5):F796-F808

Date

09/15/2020

Pubmed ID

32924545

Pubmed Central ID

PMC7789982

DOI

10.1152/ajprenal.00187.2020

Scopus ID

2-s2.0-85094221372 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

To 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.

Author List

Mehrotra P, Ullah MM, Collett JA, Myers SL, Dwinell MR, Geurts AM, Basile DP

Authors

Melinda R. Dwinell PhD Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acute Kidney Injury
Animals
Inflammation
Ischemia
Kidney
Mutation
Nuclear Receptor Subfamily 1, Group F, Member 3
Rats
Rats, Inbred Lew
Recovery of Function
Reperfusion Injury
T-Lymphocytes, Regulatory
Th17 Cells