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Profiling of Permethylated Mucin O-glycans Using Matrix-assisted Laser Desorption/Ionization Time-of-flight Mass Spectrometry
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Cosmc-dependent mucin-type O-linked glycosylation is essential for podocyte function
Brian R Stotter1,2, Brianna E Talbot1, Diane E Capen3
1Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
American Journal of Physiology. Renal Physiology
|January 7, 2020
Summary
Impaired mucin-type O-linked glycosylation in kidney podocytes, due to Cosmc deficiency, causes severe kidney disease. This suggests a crucial, cell nonautonomous role for O-glycosylation in maintaining podocyte function and overall kidney health.
Area of Science:
- Molecular Biology
- Nephrology
- Glycobiology
Background:
- Mucin-type O-linked glycosylation is vital for protein stability and function.
- This process requires C1GalT1 (T synthase) and its chaperone Cosmc.
- C1GalT1 mutations are linked to renal failure, but the precise mechanisms are unclear.
Purpose of the Study:
- To investigate if impaired Cosmc-dependent O-glycosylation in podocytes is sufficient to cause kidney disease.
- To elucidate the role of Cosmc in podocyte function and kidney health.
Main Methods:
- Generation and phenotyping of podocyte-specific Cosmc knockout mice.
- Examination of female heterozygous mice with mosaic Cosmc inactivation.
- Glomerular transcriptome analysis and ultrastructural examination of podocytes.
Main Results:
- Podocyte-specific Cosmc deletion led to severe albuminuria, podocyte loss, glomerular sclerosis, and progressive renal failure.
- Transcriptome analysis revealed altered cell adhesion, extracellular matrix, and chemokine signaling pathways.
- Loss of O-glycoprotein podoplanin and gain of Tn antigen on podocalyxin were observed.
Conclusions:
- Mucin-type O-glycosylation is essential for podocyte function and kidney health.
- Cosmc deficiency in podocytes is sufficient to cause severe kidney disease.
- A cell nonautonomous mechanism is implicated in maintaining podocyte function via O-glycoproteins.
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