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
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
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Research Article Nephrology

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

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.

Authors

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

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Figure 2

miR-214 deletion aggravates cyst growth in Pkd2-KO mice.

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miR-214 deletion aggravates cyst growth in Pkd2-KO mice. To determine th...
To determine the role of miR-214 in ADPKD, we generated Pkd2-KO miR-214+/+ (Pkd2-KO) mice and Pkd2-KO miR-214–/– mice. (A) Q-PCR analysis showing that Pkd2 expression was reduced equally in Pkd2-KO (green circles, n = 8) and Pkd2-KO miR-214–/– (red circles, n = 8) kidneys compared with noncystic control kidneys (black circles, n = 3), indicating equivalent recombination. (B) Q-PCR analysis showed miR-214 upregulation in Pkd2-KO kidneys (green circles, n = 8) compared with control kidneys (black circles, n = 3). As expected, miR-214 expression was abolished in Pkd2-KO miR-214–/– mice (red circles, n = 8). (C) Kaplan-Meier survival curves of Pkd2-KO miR-214–/– mice (red line, n = 21) and Pkd2-KO mice (green line, n = 20). The median survival was reduced in Pkd2-KO miR-214–/– mice compared with Pkd2-KO mice. (D) H&E-stained kidney sections of 35-day-old Pkd2-KO and Pkd2-KO miR-214–/– mice are shown. (E) Kidney weight/body weight (KW/BW) ratio and (F) BUN levels of 35-day-old Pkd2-KO miR-214–/– mice (n = 9–10) and Pkd2-KO (n = 8–9) mice are shown. *P < 0.05; 1-way ANOVA, Tukey’s multiple-comparisons test (A and B); Mantel-Cox test (C); Student’s unpaired t test (E and F); error bars indicate SEM.