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BMC Nephrol. 2015 Apr 14;16:55. doi: 10.1186/s12882-015-0053-1.

Loss of Dgcr8-mediated microRNA expression in the kidney results in hydronephrosis and renal malformation.

Author information

1
Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. malte.bartram@uk-koeln.de.
2
Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. claudia.dafinger@uk-koeln.de.
3
Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. sandra.habbig@uk-koeln.de.
4
Department of Pediatrics, University of Cologne, Cologne, Germany. sandra.habbig@uk-koeln.de.
5
Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. thomas.benzing@uk-koeln.de.
6
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. thomas.benzing@uk-koeln.de.
7
Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. thomas.benzing@uk-koeln.de.
8
Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. bernhard.schermer@uk-koeln.de.
9
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. bernhard.schermer@uk-koeln.de.
10
Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. bernhard.schermer@uk-koeln.de.
11
Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, Cologne, 50937, Germany. roman-ulrich.mueller@uk-koeln.de.
12
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. roman-ulrich.mueller@uk-koeln.de.
13
Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. roman-ulrich.mueller@uk-koeln.de.

Abstract

BACKGROUND:

Small non-coding RNA molecules (miRNAs) play a pivotal role in regulating gene expression in development. miRNAs regulate key processes at the cellular level and thereby influence organismal and tissue development including kidney morphogenesis. A miRNA molecule is initially synthesized as a longer hairneedle-shaped RNA transcript and then processed through an enzymatic complex that contains the RNA-processing enzyme Drosha and its essential interactor Dgcr8. Resulting pre-miRNAs are then cleaved by Dicer. Recent data showed that loss of Dicer resulted in severe developmental kidney phenotypes. However, as Dicer has multiple miRNA-independent functions, it was not entirely clear whether the observed renal phenotypes could be exclusively attributed to a lack of miRNA expression.

METHODS:

We analyzed the role of miRNAs in kidney development by conditional gene deletion of Dgcr8 in the developing kidney using a transgenic mouse line that expresses Cre recombinase in the distal nephron and derivatives of the ureteric bud in kidney development.

RESULTS:

Animals with a gene deletion of Dgcr8 in these tissues developed severe hydronephrosis, kidney cysts, progressive renal failure and premature death within the first two months after birth, a phenotype strongly resembling Dicer deletion.

CONCLUSIONS:

Here we show that conditional gene deletion of the essential miRNA-processing enzyme Dgcr8 in the developing renal tubular system results in severe developmental defects and kidney failure. These data confirm earlier findings obtained in Dicer knock-out animals and clearly illustrate the essential role of miRNAs in kidney development. The data suggests that miRNA dysregulation may play an important, yet ill-defined role in the pathogenesis of inborn defects of the genitourinary system and indicate that miRNA defects may be causative in the development of human disease.

PMID:
25881298
PMCID:
PMC4445526
DOI:
10.1186/s12882-015-0053-1
[Indexed for MEDLINE]
Free PMC Article

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