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Conditional loss of kidney microRNAs results in congenital anomalies of the kidney and urinary tract (CAKUT)

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Abstract

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.

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Acknowledgments

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the KspCre-expressing mouse line, to Michael J. Caplan for providing PKD1 cDNA and to Frank Costantini for sharing unpublished data.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.

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Authors and Affiliations

  1. Department 2 of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    Malte P. Bartram, Martin Höhne, Claudia Dafinger, Linus A. Völker, Marc Albersmeyer, Julia Heiss, Volker Burst, Max C. Liebau, Thomas Benzing, Bernhard Schermer & Roman-Ulrich Müller

  2. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

    Hella Brönneke, Thomas Benzing, Bernhard Schermer & Roman-Ulrich Müller

  3. Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany

    Martin Höhne, Thomas Benzing, Bernhard Schermer & Roman-Ulrich Müller

  4. Institute for Pathology, Diagnostic and Experimental Nephropathology Unit, University of Cologne, Cologne, Germany

    Heike Göbel

  5. Department of Pediatrics, University of Cologne, Cologne, Germany

    Max C. Liebau

  6. Department of Nephrology and Hypertension, Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der LMU, Munich, Germany

    Marc Albersmeyer

  7. Department 2 of Internal Medicine, University Hospital Cologne, 50937, Cologne, Germany

    Bernhard Schermer

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  1. Malte P. Bartram
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  2. Martin Höhne
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  10. Max C. Liebau
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  11. Thomas Benzing
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Correspondence to Bernhard Schermer.

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Bartram, M.P., Höhne, M., Dafinger, C. et al. Conditional loss of kidney microRNAs results in congenital anomalies of the kidney and urinary tract (CAKUT). J Mol Med 91, 739–748 (2013). https://doi.org/10.1007/s00109-013-1000-x

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  • DOI: https://doi.org/10.1007/s00109-013-1000-x

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