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

医学 脚(韵律) 足细胞 N-乙酰氨基葡萄糖 细胞生物学 内科学 生物化学 蛋白尿 生物 哲学 语言学
作者
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
出处
期刊:Nephrology Dialysis Transplantation [Oxford University Press]
卷期号:32 (9): 1477-1487 被引量:24
标识
DOI:10.1093/ndt/gfw463
摘要

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