Conditional loss of kidney microRNAs results in congenital anomalies of the kidney and urinary tract (CAKUT)
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MicroRNAs have emerged as essential regulators of gene expression and may play important roles in a variety of human disorders. To understand the role of microRNA-mediated gene regulation in the kidney, we deleted the microRNA-processing enzyme Dicer in developing renal tubules and parts of the ureteric bud in mice. Genetic deletion of Dicer resulted in renal failure and death of the animals at 4–6 weeks of age. Interestingly, the kidneys of microRNA-deficient animals were small due to a reduced number of nephrons and showed massive hydronephrosis due to ureteropelvic junction obstruction. This phenotype is reminiscent of congenital anomalies of the kidney and urinary tract (CAKUT), an important group of human disorders characterized by a combination of renal hypoplasia with congenital abnormalities of the urinary tract. We used metanephric kidney cultures to examine the developmental defects underlying these pathologies. Dicer knockout kidneys showed a significant reduction of tubular branching explaining renal hypoplasia. Moreover, the ureters of these kidneys showed an altered morphology and impaired motility. These functional changes went along with altered expression of smooth muscle actin implying a defect in the differentiation of ureteric smooth muscle cells. In addition, we show the polycystic kidney disease gene Pkd1 to be a target of miR-20 implying that this interaction may contribute to the molecular basis for the cystogenesis in our model. In conclusion, these data demonstrate an essential role for microRNA-dependent gene regulation in mammalian kidney development and suggest that deregulation of microRNAs may underlie CAKUT, the most important group of renal disorders in humans.
KeywordsKidney Dicer MicroRNA Pkd1 Smooth muscle CAKUT
This work was supported by the Deutsche Forschungsgemeinschaft [grant numbers SCHE1562/1 and SFB832 to B.S.; BE2212, SFB635, and SFB829 to T.B.] and by the Center for Molecular Medicine Cologne [to T.B. and B.S.]. We are grateful to Peter Igarashi for providing the KspCre-expressing mouse line, to Michael J. Caplan for providing PKD1 cDNA and to Frank Costantini for sharing unpublished data. We would like to thank Katrin Walter, Ruth Herzog, Stefanie Keller, Sonja Kunath, Nadine Urban, and Bettina Maar for excellent technical support with the animal study and microRNA experiments.
Conflict of interest
The authors declare that they have no conflict of interests.
- 30.Havens MA, Reich AA, Duelli DM, Hastings ML (2012) Biogenesis of mammalian microRNAs by a non-canonical processing pathway. Nucleic Acids ResGoogle Scholar
- 33.Waters AM, Rosenblum ND (2012) Overview of congenital anomalies of the kidney and urinary tract (CAKUT). UpToDate, Waltham, MAGoogle Scholar
- 40.Kang H, Davis-Dusenbery BN, Nguyen PH, Lal A, Lieberman J, Van Aelst L, Lagna G, Hata A (2012) Bone morphogenetic protein 4 promotes vascular smooth muscle contractility by activating microRNA-21 (miR-21), which down-regulates expression of family of dedicator of cytokinesis (DOCK) proteins. J Biol Chem 287:3976–3986PubMedCrossRefGoogle Scholar