Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-β functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.

中文翻译：

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靶向 WIP1 磷酸酶可促进实验性塌陷性肾小球病的部分缓解


塌陷性局灶节段性肾小球硬化症 (FSGS)，也称为塌陷性肾小球病 (CG)，是 FSGS 最具侵袭性的变体，其特点是快速进展为肾衰竭。了解 CG 发病机制是开发靶向治疗的关键一步。先前的研究表明端粒酶蛋白成分 TERT 与 CG 发病机制有关，因为成年小鼠中转基因 TERT 表达导致的 CG 类似于人类原发性 CG 和 HIV 相关肾病 (HIVAN) 中所见的 CG。在这里，我们使用端粒酶诱导的 CG 小鼠模型（i-TERTci 小鼠）来确定抑制 CG 发病机制的机制。 WIP1 磷酸酶（一种在负反馈环中起作用的 p53 靶标）失活可阻止 i-TERTci 小鼠疾病的发生。 WIP1 缺陷时疾病发生的抑制与衰老增强相关，并且需要转化生长因子-β 功能。然后评估药物治疗在 i-TERTci 小鼠和 HIVAN 小鼠模型（Tg26 小鼠）中减轻疾病严重程度的功效。在具有 CG 的端粒酶小鼠或 Tg26 小鼠中，对 WIP1 酶活性进行药物抑制可促进蛋白尿的部分缓解并改善肾脏组织病理学特征。组织学以及高通量测序方法进一步表明，选择性抑制 WIP1 不会促进肾脏纤维化或炎症。因此，我们的研究结果表明，靶向 WIP1 可能是 CG 患者的有效治疗策略。