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Podocyte-Selective Deletion of Dicer Induces Proteinuria and Glomerulosclerosis
Open accessAbstract
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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“For example, podocyte-specific inactivation of Dicer, one of the enzymes responsible for production of microRNAs, results in proteinuria and glomerulosclerosis196.”
From The gut microbiota and the brain–gut–kidney axis in hypertension and chronic kidney disease (2018) · cites this paper as [196]
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Metadata
- 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)
- ORCID
- Venue
- Journal of the American Society of Nephrology
- Published
- 2008-11
- Volume
- 19
- Issue
- 11
- Pages
- 2159-2169
- ISSN
- 1046-6673 (ISSN-L)
- PMC
- PMC2573016
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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