Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, China.
Department of Biology, Southern University of Science and Technology, 518000, Shenzhen, P.R. China.
Cell Death Dis. 2020 May 13;11(5):364. doi: 10.1038/s41419-020-2539-4.
Ras homolog enriched in brain (Rheb1), a small GTPase, plays a crucial role in regulating cell growth, differentiation, and survival. However, the role and mechanisms for Rheb1 in tubular cell survival and acute kidney injury (AKI) remain unexplored. Here we found that Rheb1 signaling was activated in kidney tubule of AKI patients and cisplatin-treated mice. A mouse model of tubule-specific deletion of Rheb1 (Tubule-Rheb1) was generated. Compared to control littermates, Tubule-Rheb1 mice were phenotypically normal within 2 months after birth but developed more severe kidney dysfunction, tubular cell death including apoptosis, necroptosis and ferroptosis, mitochondrial defect and less PGC-1α expression after cisplatin injection. In primary cultured tubular cells, Rheb1 ablation exacerbated cisplatin-induced cell death and mitochondrial defect. Furthermore, haploinsufficiency for Tsc1 in tubular cells led to Rheb1 activation and mitigated cisplatin-induced cell death, mitochondrial defect and AKI. Together, this study uncovers that Rheb1 may protect against cisplatin-induced tubular cell death and AKI through maintaining mitochondrial homeostasis.
脑富集 Ras 同源物（Rheb1）是一种小分子 GTPase，在调节细胞生长、分化和存活方面发挥着关键作用。然而，Rheb1 在管状细胞存活和急性肾损伤（AKI）中的作用和机制仍未被探索。在这里，我们发现 Rheb1 信号在 AKI 患者和顺铂处理的小鼠的肾小管中被激活。生成了一种肾小管特异性缺失 Rheb1（肾小管-Rheb1）的小鼠模型。与对照同窝仔相比，Tubule-Rheb1 小鼠在出生后 2 个月内表型正常，但在注射顺铂后，肾功能衰竭更严重，肾小管细胞死亡包括凋亡、坏死性凋亡和铁死亡，线粒体缺陷和较少的 PGC-1α 表达。在原代培养的肾小管细胞中，Rheb1 缺失加剧了顺铂诱导的细胞死亡和线粒体缺陷。此外，肾小管细胞中 Tsc1 的杂合不足导致 Rheb1 激活，并减轻了顺铂诱导的细胞死亡、线粒体缺陷和 AKI。总之，这项研究揭示了 Rheb1 可能通过维持线粒体稳态来防止顺铂诱导的肾小管细胞死亡和 AKI。
