Mutation of RORγT reveals a role for Th17 cells in both injury and recovery from renal ischemia-reperfusion injury.

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.

• Authors: Purvi Mehrotra, Md Mahbub Ullah, Jason A Collett, Sarah L Myers, Melinda R Dwinell, Aron M Geurts, David P Basile
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 319 Issue 5 Pg. F796-F808 (11 01 2020) ISSN: 1522-1466 [Electronic] United States
• PMID: 32924545 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Nuclear Receptor Subfamily 1, Group F, Member 3
• Rorc protein, rat

Topics

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