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