Department of Medicine, Shiga University of Medical Science, Shiga, Japan.
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nephrol Dial Transplant. 2017 Sep 1;32(9):1477-1487. doi: 10.1093/ndt/gfw463.
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.
O-连接β-N-乙酰氨基葡萄糖修饰（O-GlcNAcylation）是细胞内蛋白质的一种翻译后修饰，作为一种营养传感器。越来越多的证据表明，它在各种哺乳动物组织的生理和病理中具有重要意义。本研究探讨了 O-GlcNAcylation 在足细胞功能和发育中的生理作用。
O-连接糖基转移酶（Ogt）是 O-GlcNAcylation 的关键酶，位于 X 染色体上。为了在足细胞中消除 O-GlcNAcylation，我们生成了先天性和他莫昔芬（TM）诱导的足细胞特异性 Ogt 敲除小鼠（Podo-Ogt y/- 和 TM-Podo-Ogt y/-，分别），并分析了它们的肾脏表型。
Podo-Ogt y/- 小鼠在出生时表现出正常的足细胞形态。然而，它们在 8 周龄时出现白蛋白尿，直至 32 周龄时逐渐增加。在 32 周龄的 Podo-Ogt y/- 小鼠中，组织学观察到肾小球硬化、蛋白尿相关的肾小管间质病变和明显改变的足细胞足突，足细胞蛋白表达减少。接下来，我们通过在 8 周龄的 TM-Podo-Ogt y/- 小鼠中注射 TM 诱导成年后足细胞中 Ogt 基因缺失。与 Podo-Ogt y/- 小鼠不同，诱导的 TM-Podo-Ogt y/- 小鼠没有发生白蛋白尿或足细胞损伤，这表明 O-GlcNAcylation 是出生后足细胞成熟形成足突所必需的。为了验证这一可能性，我们用 Bis-T-23 处理 3 周龄的 Podo-Ogt y/- 小鼠，Bis-T-23 可刺激肌动蛋白依赖性 dynamin 寡聚化、肌动蛋白聚合和随后的足细胞足突伸长。16 周龄的 Podo-Ogt y/- 小鼠用 Bis-T-23 治疗可预防白蛋白尿和足细胞损伤。
O-GlcNAcylation 是足细胞足突成熟所必需的，特别是在出生后。我们的研究为足细胞生物学和 O-GlcNAcylation 提供了新的见解。
