Blocking ribosomal protein S6 phosphorylation inhibits podocyte hypertrophy and focal segmental glomerulosclerosis.
Blocking ribosomal protein S6 phosphorylation inhibits podocyte hypertrophy and focal segmental glomerulosclerosis.
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阻断核糖体蛋白S6磷酸化抑制足细胞肥大和局灶节段性肾小球硬化。
DOI：
10.1016/j.kint.2022.02.037
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发表时间：
2022-07
影响因子：
19.6
通讯作者：
Wu, Huijuan
中科院分区：
文献类型：
--
作者：
Li, Fang;Fang, Yili;Zhuang, Qiyuan;Cheng, Meichu;Moronge, Desmond;Jue, Hao;Meyuhas, Oded;Ding, Xiaoqiang;Zhang, Zhigang;Chen, Jian-Kang;Wu, Huijuan
核糖体蛋白S6（rpS 6）磷酸化介导肾近曲小管细胞的肥大生长。然而，在局灶节段性肾小球硬化症（FSGS）的发病机制中，rpS 6磷酸化在足细胞肥大和足细胞丢失中的作用仍不明确。在这里，我们研究了rpS 6磷酸化水平在肾活检标本与FSGS患者和足细胞从阿霉素诱导的FSGS小鼠肾脏。在FSGS小鼠模型中使用遗传学和药理学方法，我们研究了rpS 6磷酸化在FSGS发展和进展过程中足细胞肥大和丢失中的作用。磷酸化rpS 6被发现在FSGS患者和阿霉素诱导的FSGS小鼠的足细胞中显著增加。肾肾小球足细胞中肾硬化症1基因的遗传缺失激活哺乳动物雷帕霉素复合物1靶向信号传导至rpS 6磷酸化，导致足细胞肥大和与FSGS患者相似的病理特征，包括足细胞损失，导致节段性肾小球硬化症。由于已知蛋白磷酸酶1负调节rpS 6磷酸化，因此用抑制剂处理增加磷酸-rpS 6水平，促进足细胞肥大并加剧FSGS病变的形成。重要的是，阻断rpS 6磷酸化（通过产生表达不可磷酸化的rpS 6的同源rpS 6敲入小鼠或通过用抑制剂抑制核糖体蛋白S6激酶1介导的rpS 6磷酸化）显著减弱足细胞肥大，抑制足细胞损失，并减弱FSGS损伤的形成。因此，我们的研究提供了遗传学和药理学证据，表明特异性靶向rpS 6磷酸化可以通过抑制足细胞肥大和相关的足细胞耗竭来减弱FSGS病变的发展。
Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion.
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影响因子：
5.2
作者：
Kriz W;Hähnel B;Hosser H;Rösener S;Waldherr R
通讯作者：
Waldherr R
影响因子：
2.9
作者：
Jefferson JA;Shankland SJ
通讯作者：
Shankland SJ
影响因子：
4.2
作者：
Campbell KN;Tumlin JA
通讯作者：
Tumlin JA
影响因子：
19.6
作者：
Kim, YH;Goyal, M;Wiggins, R
通讯作者：
Wiggins, R
影响因子：
82.9
作者：
Canaud, Guillaume;Bienaime, Frank;Terzi, Fabiola
通讯作者：
Terzi, Fabiola