HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation.

Published

Journal Article

Hypoxia promotes tubulointerstitial inflammation in the kidney. Although hypoxia inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia, the exact mechanisms through which HIF-1α modulates the induction of tubulointerstitial inflammation are still largely unclear. We demonstrated tubulointerstitial inflammation and increased tubular HIF-1α expression in murine models of ischemia/reperfusion injury and unilateral ureteral obstruction. Increased expression of HIF-1α in tubular epithelial cells was associated with selective shedding of microRNA-23a (miRNA-23a)-enriched exosomes in vivo and systemic inhibition of miRNA-23a prior to ischemia/reperfusion injury attenuated tubulointerstitial inflammation. In vitro, uptake of miRNA-23a-enriched exosomes by macrophages triggered their reprogramming into a pro-inflammatory state via suppression of the ubiquitin editor A20. To confirm the effect of miRNA-23a-containing exosomes on tubulointerstitial inflammation, we exposed tubular epithelial cells to hypoxic conditions to promote the release of miRNA-23a-containing exosomes. Injection of these miRNA-23a-enriched exosomes into uninjured renal parenchyma resulted in increased inflammatory infiltration in vivo. Taken together, our studies demonstrate that the HIF-1α-dependent release of miRNA-23a-enriched exosomes from hypoxic tubular epithelial cells activates macrophages to promote tubulointerstitial inflammation. Blockade of exosome-mediated miRNA-23a transfer between tubular epithelial cells and macrophages may serve as a novel therapeutic approach to ameliorate tubulointerstitial inflammation.

Full Text

Duke Authors

Cited Authors

  • Li, Z-L; Lv, L-L; Tang, T-T; Wang, B; Feng, Y; Zhou, L-T; Cao, J-Y; Tang, R-N; Wu, M; Liu, H; Crowley, SD; Liu, B-C

Published Date

  • February 2019

Published In

Volume / Issue

  • 95 / 2

Start / End Page

  • 388 - 404

PubMed ID

  • 30551896

Pubmed Central ID

  • 30551896

Electronic International Standard Serial Number (EISSN)

  • 1523-1755

Digital Object Identifier (DOI)

  • 10.1016/j.kint.2018.09.013

Language

  • eng

Conference Location

  • United States