| Authors |
Shi S, Yu L, Chiu C, Sun Y, Chen J, Khitrov G, Merkenschlager M, Holzman LB,
Zhang W, Mundel P, Bottinger EP
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| Submitted By |
Erwin Bottinger on 2/8/2009 |
| Status |
Published |
| Journal |
Journal of the American Society of Nephrology : JASN |
| Year |
2008 |
| Date Published |
11/1/2008 |
| Volume : Pages |
19(11) : 2159 - 2169 |
| PubMed Reference |
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| Abstract |
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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