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Podocyte-Selective Deletion of Dicer Induces Proteinuria and Glomerulosclerosis

Shaolin Shi^*, Liping Yu^*, Celine Chiu^*, Yezhou Sun^*, Jin Chen^*, Greg Khitrov^*, Matthias Merkenschlager, Lawrence B. Holzman, Weijia Zhang^*, Peter Mundel^* and Erwin P. Bottinger^*,

^* Division of Nephrology, Department of Medicine, and Charles R. Bronfman Institute for Personalized Medicine, Mount Sinai School of Medicine, New York, New York; Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom; and Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, Michigan

Correspondence: Dr. Erwin Bottinger, Charles R. Bronfman Institute for Personalized Medicine, Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029. Phone: 212-241-0800; Fax: 212-849-2643; E-mail: erwin.bottinger{at}mssm.edu; or Dr. Shaolin Shi, Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029. Phone: 212-241-0482; Fax: 212-849-2643; E-mail: shaolin.shi{at}mssm.edu

Received for publication March 20, 2008. Accepted for publication July 6, 2008.

Dicer is an enzyme that generates microRNA (miRNA), which are small, noncoding RNA that function as important regulators of gene and protein expression. For exploration of the functional roles of miRNA in glomerular biology, Dicer was inactivated selectively in mouse podocytes. Mutant mice developed proteinuria 4 to 5 weeks after birth and died several weeks later, presumably from kidney failure. Multiple abnormalities were observed in glomeruli of mutant mice, including foot process effacement, irregular and split areas of the glomerular basement membrane, podocyte apoptosis and depletion, mesangial expansion, capillary dilation, and glomerulosclerosis. Gene profiling revealed upregulation of 190 genes in glomeruli isolated from mutant mice at the onset of proteinuria compared with control littermates. Target sequences for 16 miRNA were significantly enriched in the 3'-untranslated regions of the 190 upregulated genes. Further suggesting validity of the in silico analysis, six of the eight top-candidate miRNA were identified in miRNA libraries generated from podocyte cultures; these included four members of the mir-30 miRNA family, which are known to degrade target transcripts directly. Among 15 upregulated target genes of the mir-30 miRNA, four genes known to be expressed and/or functional in podocytes were identified, including receptor for advanced glycation end product, vimentin, heat-shock protein 20, and immediate early response 3. Receptor for advanced glycation end product and immediate early response 3 are known to mediate podocyte apoptosis, whereas vimentin and heat-shock protein-20 are involved in cytoskeletal structure. Taken together, these results provide a knowledge base for ongoing investigations to validate functional roles for the mir-30 miRNA family in podocyte homeostasis and podocytopathies.

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Dicer Cuts the Kidney

J.J. David Ho and Philip A. Marsden
J. Am. Soc. Nephrol. 2008 19: 2043-2046. [Full Text] [PDF]

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				J.J. D. Ho and P. A. Marsden Dicer Cuts the Kidney J. Am. Soc. Nephrol., November 1, 2008; 19(11): 2043 - 2046. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673