Department of Endocrinology, 2(nd) Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan, Nanjing, Jiangsu, China.
Department of Endocrinology, 2(nd) Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan, Nanjing, Jiangsu, China; Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, No. 666 Shengli Road, Nantong 226001, China.
Cell Signal. 2024 Dec;124:111451. doi: 10.1016/j.cellsig.2024.111451. Epub 2024 Oct 9.
Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.
足细胞衰老可导致糖尿病肾病（DKD）中持续的足细胞损伤和白蛋白尿，但具体机制尚不清楚。本研究通过对 DKD 患者和小鼠的足细胞进行免疫组化染色，证实了足细胞衰老的存在。在糖尿病小鼠中敲除雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）下游的 Ras 相关蛋白 Ras homolog enriched in brain 1（Rheb1）可加重足细胞衰老和损伤，但减轻了由 Tsc1 缺失诱导的足细胞特异性 mTORC1 激活所致的足细胞损伤。在培养的足细胞中，Rheb1 的敲低可显著加速足细胞衰老，而与 mTORC1 无关。在机制上，DKD 患者足细胞中丙酮酸脱氢酶（PDH）的磷酸化与足细胞衰老相关。Rheb1 缺失降低了 ATP、线粒体膜电位和部分呼吸链复合物成分，并增加了 ROS 产生和 PDH 磷酸化，这表明线粒体功能障碍，无论是在体外还是体内。此外，Rheb1 与 Atp5f1c 相互作用，并在高糖条件下调节其乙酰化。总之，Rheb1 缺失通过促进 Atp5f1c 乙酰化导致线粒体功能障碍和加速足细胞衰老，这种作用不依赖于 mTORC1，为 DKD 的治疗提供了实验依据。
