TGF-? promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration.

ABSTRACT: TGF-? signals through a receptor complex composed of 2 type I and 2 type II (TGF-?RII) subunits. We investigated the role of macrophage TGF-? signaling in fibrosis after AKI in mice with selective monocyte/macrophage TGF-?RII deletion (macrophage TGF-?RII-/- mice). Four weeks after injury, renal TGF-?1 expression and fibrosis were higher in WT mice than macrophage TGF-?RII-/- mice, which had decreased renal macrophages. The in vitro chemotactic response to f-Met-Leu-Phe was comparable between bone marrow-derived monocytes (BMMs) from WT and macrophage TGF-?RII-/- mice, but TGF-?RII-/- BMMs did not respond to TGF-?. We then implanted Matrigel plugs suffused with either f-Met-Leu-Phe or TGF-?1 into WT or macrophage TGF-?RII-/- mice. After 6 days, f-Met-Leu-Phe induced similar macrophage infiltration into the Matrigel plugs of WT and macrophage TGF-?RII-/- mice, but TGF-? induced infiltration only in WT mice. We further determined the number of labeled WT or TGF-?RII-/- BMMs infiltrating into WT kidneys 20 days after ischemic injury. There were more labeled WT BMMs than TGF-?RII-/- BMMs. Therefore, macrophage TGF-?RII deletion protects against the development of tubulointerstitial fibrosis following severe ischemic renal injury. Chemoattraction of macrophages to the injured kidney through a TGF-?/TGF-?RII axis is a heretofore undescribed mechanism by which TGF-? can mediate renal fibrosis during progressive renal injury.

SUBMITTER: Chung S 

PROVIDER: S-EPMC6238749 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature