Suppression of microRNA Activity in Kidney Collecting Ducts Induces Partial Loss of Epithelial Phenotype and Renal Fibrosis.

Abstract

microRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. The physiologic function of these noncoding RNAs in postnatal renal tubules still remains unclear. Surprisingly, they appear to be dispensable for mammalian proximal tubule (PT) function. Here, we examined the effects of miRNA suppression in collecting ducts (CDs). To conclusively evaluate the role of miRNAs, we generated three mouse models with CD-specific inactivation of key miRNA pathway genes Dicer, Dgcr8, and the entire Argonaute gene family (Ago1, 2, 3, and 4). Characterization of these three mouse models revealed that inhibition of miRNAs in CDs spontaneously evokes a renal tubule injury-like response, which culminates in progressive tubulointerstitial fibrosis (TIF) and renal failure. Global miRNA profiling of microdissected renal tubules showed that miRNAs exhibit segmental distribution along the nephron and CDs. In particular, the expression of miR-200c is nearly 70-fold higher in CDs compared with PTs. Accordingly, miR-200s are downregulated in Dicer-KO CDs, its direct target genes Zeb1, Zeb2, and Snail2 are upregulated, and miRNA-depleted CDs undergo partial epithelial-to-mesenchymal transition (EMT). Thus, miRNAs are essential for CD homeostasis. Downregulation of CD-enriched miRNAs and the subsequent induction of partial EMT may be a new mechanism for TIF progression.

• Authors: Sachin Hajarnis, Matanel Yheskel, Darren Williams, Thomas Brefort, Bob Glaudemans, Huguette Debaix, Michel Baum, Olivier Devuyst, Vishal Patel
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 29 Issue 2 Pg. 518-531 (02 2018) ISSN: 1533-3450 [Electronic] United States
• PMID: 29021386 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society of Nephrology.

Chemical References

• AGO4 protein, mouse
• Ago1 protein, mouse
• Ago2 protein, mouse
• Ago3 protein, mouse
• Argonaute Proteins
• Dgcr8 protein, mouse
• Eukaryotic Initiation Factors
• MicroRNAs
• Mirn200 microRNA, mouse
• RNA-Binding Proteins
• Snai1 protein, mouse
• Snail Family Transcription Factors
• ZEB1 protein, mouse
• ZEB2 protein, mouse
• Zinc Finger E-box Binding Homeobox 2
• Zinc Finger E-box-Binding Homeobox 1
• Dicer1 protein, mouse
• Ribonuclease III
• DEAD-box RNA Helicases

Topics

• Animals
• Argonaute Proteins (genetics)
• Cell Line
• DEAD-box RNA Helicases (genetics)
• Down-Regulation
• Epithelial-Mesenchymal Transition (genetics)
• Epithelium (metabolism, pathology)
• Eukaryotic Initiation Factors (genetics)
• Female
• Fibrosis
• Gene Expression
• Homeostasis (genetics)
• Kidney Tubules, Collecting (metabolism, pathology)
• Kidney Tubules, Proximal (metabolism)
• Male
• Mice
• Mice, Knockout
• MicroRNAs (antagonists & inhibitors, genetics)
• Phenotype
• RNA-Binding Proteins (genetics)
• Ribonuclease III (genetics)
• Snail Family Transcription Factors (genetics)
• Zinc Finger E-box Binding Homeobox 2 (genetics)
• Zinc Finger E-box-Binding Homeobox 1 (genetics)