Deficits in sialylation impair podocyte maturation
- PMID: 22745475
- PMCID: PMC3402283
- DOI: 10.1681/ASN.2011090947
Deficits in sialylation impair podocyte maturation
Abstract
The role of sialylation in kidney biology is not fully understood. The synthesis of sialoglycoconjugates, which form the outermost structures of animal cells, requires CMP-sialic acid, which is a product of the nuclear enzyme CMAS. We used a knock-in strategy to create a mouse with point mutations in the canonical nuclear localization signal of CMAS, which relocated the enzyme to the cytoplasm of transfected cells without affecting its activity. Although insufficient to prevent nuclear entry in mice, the mutation led to a drastically reduced concentration of nuclear-expressed enzyme. Mice homozygous for the mutation died from kidney failure within 72 hours after birth. The Cmas(nls) mouse exhibited podocyte foot process effacement, absence of slit diaphragms, and massive proteinuria, recapitulating features of nephrin-knockout mice and of patients with Finnish-type congenital nephrotic syndrome. Although the Cmas(nls) mouse displayed normal sialylation in all organs including kidney, a critical shortage of CMP-sialic acid prevented sialylation of nephrin and podocalyxin in the maturing podocyte where it is required during the formation of foot processes. Accordingly, the sialylation defects progressed with time and paralleled the morphologic changes. In summary, sialylation is critical during the development of the glomerular filtration barrier and required for the proper function of nephrin. Whether altered sialylation impairs nephrin function in human disease requires further study.
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Comment in
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Basic research: Sialylation of podocyte proteins is critical for GFB development.Nat Rev Nephrol. 2012 Sep;8(9):494. doi: 10.1038/nrneph.2012.157. Epub 2012 Jul 17. Nat Rev Nephrol. 2012. PMID: 22801947 No abstract available.
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References
-
- Gelberg H, Healy L, Whiteley H, Miller LA, Vimr E: In vivo enzymatic removal of alpha 2—>6-linked sialic acid from the glomerular filtration barrier results in podocyte charge alteration and glomerular injury. Lab Invest 74: 907–920, 1996 - PubMed
-
- Crocker PR, Varki A: Siglecs, sialic acids and innate immunity. Trends Immunol 22: 337–342, 2001 - PubMed
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