Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression

Ronak Lakhia, Matanel Yheskel, Andrea Flaten, Harini Ramalingam, Karam Aboudehen, Silvia Ferrè, Laurence Biggers, Abheepsa Mishra, Christopher Chaney, Darren P. Wallace, Thomas Carroll, Peter Igarashi, Vishal Patel

Research output: Contribution to journalArticlepeer-review

Abstract

Renal cysts are the defining feature of autosomal dominant polycystic kidney disease (ADPKD); however, the substantial interstitial inflammation is an often-overlooked aspect of this disorder. Recent studies suggest that immune cells in the cyst microenvironment affect ADPKD progression. Here we report that microRNAs (miRNAs) are new molecular signals in this crosstalk. We found that miR-214 and its host long noncoding RNA Dnm3os are upregulated in orthologous ADPKD mouse models and cystic kidneys from humans with ADPKD. In situ hybridization revealed that interstitial cells in the cyst microenvironment are the primary source of miR-214. While genetic deletion of miR-214 does not affect kidney development or homeostasis, surprisingly, its inhibition in Pkd2- and Pkd1-mutant mice aggravates cyst growth. Mechanistically, the proinflammatory TLR4/IFN-γ/STAT1 pathways transactivate the miR-214 host gene. miR-214, in turn as a negative feedback loop, directly inhibits Tlr4. Accordingly, miR-214 deletion is associated with increased Tlr4 expression and enhanced pericystic macrophage accumulation. Thus, miR-214 upregulation is a compensatory protective response in the cyst microenvironment that restrains inflammation and cyst growth.

Original languageEnglish (US)
Article numbere133785
JournalJCI Insight
Volume5
Issue number7
DOIs
StatePublished - Apr 9 2020

Bibliographical note

Funding Information:
The work is supported by the National Institutes of Health (R01DK102572) and the Department of Defense (D01 W81XWH1810673) to VP. RL is supported by National Institutes of Health (K08DK117049). SF was supported by the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Innovative Research Support Award. We thank the UT Southwestern O’Brien Kidney Research Core Center (P30DK079328) and UT Southwestern Bioinformatics Core Facility for providing critical reagents and services. We thank the PKD Biomarkers and Biomaterials Core of the University of Kansas Medical Center (P30DK106912) and the Mayo Translational PKD center for providing the human ADPKD samples.

Funding Information:
The work is supported by the National Institutes of Health (R01DK102572) and the Department of Defense (D01 W81XWH1810673) to VP. RL is supported by National Institutes of Health (K08DK117049). SF was supported by the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research Innovative Research Support Award. We thank the UT Southwestern O'Brien Kidney Research Core Center (P30DK079328) and UT Southwestern Bioinformatics Core Facility for providing critical reagents and services. We thank the PKD Biomarkers and Biomaterials Core of the University of Kansas Medical Center (P30DK106912) and the Mayo Translational PKD center for providing the human ADPKD samples.

Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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