Cosmc-dependent mucin-type O-linked glycosylation is essential for podocyte function

Brian R. Stotter, Brianna E. Talbot, Diane E. Capen, Nadine Artelt, Junwei Zeng, Yasuyuki Matsumoto, Nicole Endlich, Richard D. Cummings, Johannes S. Schlondorff

Research output: Contribution to journalArticle

Abstract

Mucin-type O-linked glycosylation, a posttranslational modification affecting the stability and biophysical characteristics of proteins, requires C1GalT1 (T synthase) and its obligate, X-linked chaperone Cosmc. Hypomorphic C1GalT1 mutations cause renal failure via not yet established mechanisms. We hypothesize that impaired Cosmc-dependent O-glycosylation in podocytes is sufficient to cause disease. Podocyte-specific Cosmc knockout mice were generated and phenotyped to test this hypothesis. Female heterozygous mice displaying mosaic inactivation of Cosmc in podocytes due to random X-linked inactivation were also examined. Mice with podocyte-specific Cosmc deletion develop profound albuminuria, foot process effacement, glomerular sclerosis, progressive renal failure, and impaired survival. Glomerular transcriptome analysis reveals early changes in cell adhesion, extracellular matrix organization, and chemokine-mediated signaling pathways, coupled with podocyte loss. Expression of the O-glycoprotein podoplanin was lost, while Tn antigen, representing immature O-glycans, was most abundantly found on podocalyxin. In contrast to hemizygous male and homozygous female animals, heterozygous female mosaic animals developed only mild albuminuria, focal foot process effacement, and nonprogressive kidney disease. Ultrastructurally, Cosmc-deficient podocytes formed Tn antigen-positive foot processes interdigitating with those of normal podocytes but not with other Cosmc-deficient cells. This suggests a cell nonautonomous mechanism for mucin-type O-glycoproteins in maintaining podocyte function. In summary, our findings demonstrated an essential and likely cell nonautonomous role for mucin-type O-glycosylation for podocyte function.

Original languageEnglish
Pages (from-to)F518-F530
JournalAmerican journal of physiology. Renal physiology
Volume318
Issue number2
DOIs
StatePublished - Feb 1 2020
Externally publishedYes

Keywords

  • O-linked glycosylation
  • T synthase
  • X linked
  • podocalyxin
  • podocytes

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    Stotter, B. R., Talbot, B. E., Capen, D. E., Artelt, N., Zeng, J., Matsumoto, Y., Endlich, N., Cummings, R. D., & Schlondorff, J. S. (2020). Cosmc-dependent mucin-type O-linked glycosylation is essential for podocyte function. American journal of physiology. Renal physiology, 318(2), F518-F530. https://doi.org/10.1152/ajprenal.00399.2019