Cited by 349Renal Diseases and GlomerulopathiesMicroRNA in disease regulationChronic Kidney Disease and Diabetes

Podocyte-Selective Deletion of Dicer Induces Proteinuria and Glomerulosclerosis

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Shi, Shaolin, Yu, Liping, Chiu, Celine, Sun, Yezhou, Chen, Jin, Khitrov, Greg, Merkenschlager, Matthias, Holzman, Lawrence B. +3 more·2008·Journal of the American Society of Nephrology

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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Authors
Shi, S., Yu, L., Chiu, C., Sun, Y., Chen, J., Khitrov, G., Merkenschlager, M., Holzman, L. B., Zhang, W., Mundel, P., & Bottinger, E. P.
Affiliations
Mount Sinai Hospital (US)
Venue
Journal of the American Society of Nephrology
Published
2008-11
Volume
19
Issue
11
Pages
2159-2169
ISSN
1046-6673 (ISSN-L)
OpenAlex
W2110336660
Cited by
349
References
61
Citations by year
2026: 4 · 2025: 3 · 2024: 7 · 2023: 14 · 2022: 12 · 2021: 13 · 2020: 15 · 2019: 19 · 2018: 19 · 2017: 23 · 2016: 32 · 2015: 38 · 2014: 27 · 2013: 25 · 2012: 30
FWCI
18.23
Type
journal article
Language
en
Open access
Locations
  • Journal of the American Society of Nephrology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Society of Nephrology
  • National Institutes of Health
  • National Cancer Institute (R24CA095823)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073960, U01DK060995, U01DK60995, R01DK056077, R01DK060043)
Topics
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
Dicer, microRNA, podocytes, proteinuria, glomerulosclerosis, podocyte apoptosis, miR-30 family, glomerular basement membrane, podocytopathy, vimentin, HSP20, gene expression profiling
MeSH terms
Animals, Base Sequence, Endoribonucleases, Glomerulosclerosis, Focal Segmental, Proteinuria, Apoptosis, DNA Primers, Mice, Knockout, 3' Untranslated Regions, Gene Expression Profiling, MicroRNAs, Ribonuclease III, Podocytes, Mice, DEAD-box RNA Helicases

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