Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia.
Department of Nephrology, Monash Health, Melbourne, Australia.
JCI Insight. 2019 Sep 19;4(18):99271. doi: 10.1172/jci.insight.99271.
The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles. Advanced morphometric analyses in murine and human tissues identified podocyte hypertrophy as a compensatory mechanism aiming to regulate glomerular functional integrity in response to somatic growth, podocyte depletion, and even glomerulosclerosis - all of this in the absence of detectable podocyte regeneration. In mice, pharmacological inhibition of mTOR signaling during acute podocyte loss impaired hypertrophy of remaining podocytes, resulting in unexpected albuminuria, PEC activation, and glomerulosclerosis. Exacerbated and persistent podocyte hypertrophy enabled a vicious cycle of podocyte loss and PEC activation, suggesting a limit to its beneficial effects. In summary, our data highlight a critical protective role of mTOR-mediated podocyte hypertrophy following podocyte loss in order to preserve glomerular integrity, preventing PEC activation and glomerulosclerosis.
肾小球硬化的细胞起源涉及壁层上皮细胞 (PEC) 的激活和足细胞的逐渐耗竭。虽然哺乳动物雷帕霉素靶蛋白 (mTOR) 介导的足细胞肥大被认为是肾小球疾病背景下的一个重要信号通路，但足细胞肥大作为一种防止 PEC 激活和肾小球硬化的代偿机制的作用仍知之甚少。在这项研究中，我们表明，局灶节段性肾小球硬化症 (FSGS) 和糖尿病肾病患者活检中的肾小球 mTOR 和 PEC 激活相关基因均上调且相互关联，这表明存在代偿和病理作用。在小鼠和人类组织中的高级形态计量学分析表明，足细胞肥大是一种代偿机制，旨在响应体生长、足细胞耗竭甚至肾小球硬化，调节肾小球的功能完整性——所有这些都没有检测到足细胞再生。在小鼠中，急性足细胞丢失期间 mTOR 信号的药理学抑制会损害剩余足细胞的肥大，导致意外的白蛋白尿、PEC 激活和肾小球硬化。加剧和持续的足细胞肥大导致足细胞丢失和 PEC 激活的恶性循环，表明其有益作用有限。总之，我们的数据强调了 mTOR 介导的足细胞肥大在足细胞丢失后对维持肾小球完整性、防止 PEC 激活和肾小球硬化的关键保护作用。
