O-linked β-N-acetylglucosamine modification of proteins is essential for foot process maturation and survival in podocytes.

Abstract

BACKGROUND:

O-linked β- N -acetylglucosamine modification O-GlcNAcylation) is a post-translational modification of intracellular proteins, serving as a nutrient sensor. Growing evidence has demonstrated its physiological and pathological importance in various mammalian tissues. This study examined the physiological role of O-GlcNAcylation in podocyte function and development.

METHODS:

O-GlcNAc transferase (Ogt) is a critical enzyme for O-GlcNAcylation and resides on the X chromosome. To abrogate O-GlcNAcylation in podocytes, we generated congenital and tamoxifen (TM)-inducible podocyte-specific Ogt knockout mice (Podo-Ogt y/- and TM-Podo-Ogt y/- , respectively) and analyzed their renal phenotypes.

RESULTS:

Podo-Ogt y/- mice showed normal podocyte morphology at birth. However, they developed albuminuria at 8 weeks of age, increasing progressively until age 32 weeks. Glomerular sclerosis, proteinuria-related tubulointerstitial lesions and markedly altered podocyte foot processes, with decreased podocin expression, were observed histologically in 32-week-old Podo-Ogt y/- mice. Next, we induced adult-onset deletion of the Ogt gene in podocytes by TM injection in 8-week-old TM-Podo-Ogt y/- mice. In contrast to Podo-Ogt y/- mice, the induced TM-Podo-Ogt y/- mice did not develop albuminuria or podocyte damage, suggesting a need for O-GlcNAcylation to form mature foot processes after birth. To test this possibility, 3-week-old Podo-Ogt y/- mice were treated with Bis-T-23, which stimulates actin-dependent dynamin oligomerization, actin polymerization and subsequent foot process elongation in podocytes. Albuminuria and podocyte damage in 16-week-old Podo-Ogt y/- mice were prevented by Bis-T-23 treatment.

CONCLUSIONS:

O-GlcNAcylation is necessary for maturation of podocyte foot processes, particularly after birth. Our study provided new insights into podocyte biology and O-GlcNAcylation.

• Authors: Shinya Ono, Shinji Kume, Mako Yasuda-Yamahara, Kosuke Yamahara, Naoko Takeda, Masami Chin-Kanasaki, Hisazumi Araki, Osamu Sekine, Hideki Yokoi, Masashi Mukoyama, Takashi Uzu, Shin-Ichi Araki, Hiroshi Maegawa
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 32 Issue 9 Pg. 1477-1487 (Sep 01 2017) ISSN: 1460-2385 [Electronic] England
• PMID: 28339907 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• NPHS2 protein
• N-Acetylglucosaminyltransferases
• O-GlcNAc transferase
• Acetylglucosamine

Topics

• Acetylglucosamine (chemistry)
• Animals
• Female
• Foot (physiology)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• N-Acetylglucosaminyltransferases (physiology)
• Podocytes (metabolism)
• Protein Processing, Post-Translational