Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression
| Autor: | Laurence Biggers, Thomas L. Carroll, Peter Igarashi, Ronak Lakhia, Harini Ramalingam, Vishal Patel, Silvia Ferrè, Darren P. Wallace, Karam Aboudehen, Matanel Yheskel, Abheepsa Mishra, Andrea Flaten, Christopher P. Chaney |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Autosomal dominant polycystic kidney disease Kidney development Mice Transgenic Inflammation Biology urologic and male genital diseases Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine Polycystic kidney disease Animals Cyst Cystic kidney urogenital system General Medicine Polycystic Kidney Autosomal Dominant medicine.disease MicroRNAs 030104 developmental biology 030220 oncology & carcinogenesis Cancer research medicine.symptom Signal Transduction Research Article |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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