Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease
Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease
复制标题
线粒体甘油3-磷酸脱氢酶缺乏会加剧足细胞损伤和糖尿病肾病的进展
作者：
H. Qu;Xiaoli Gong;Xiufei Liu;Rui Zhang;Yuren Wang;Bangliang Huang;LinLin Zhang;Hongting Zheng;Y. Zheng
线粒体功能对于生物能量学、代谢和信号传导是必不可少的，并且在蛋白尿肾病等疾病中受损，导致肾衰竭、心血管发病率和死亡的全球负担。防止蛋白尿的关键细胞类型是终末分化的肾小球足细胞。在这项研究中，我们的特点是线粒体甘油3-磷酸脱氢酶（mGPDH），位于线粒体内膜，在调节足细胞功能和肾小球疾病的重要性。具体而言，足细胞主导的mGPDH表达下调的患者和糖尿病肾病和阿霉素肾病小鼠的肾小球。小鼠足细胞特异性mGPDH耗竭加重糖尿病或阿霉素诱导的蛋白尿、足细胞损伤和肾小球病理。RNA测序显示，mGPDH调节受体的晚期糖基化终产物（AGEs）信号通路，和AGEs或其配体，S100 A10的抑制，保护对受损的线粒体生物能和增加活性氧产生所造成的mGPDH敲低培养的足细胞。此外，足细胞中的cDNA 3缺失减轻了mGPDH缺陷型糖尿病小鼠的肾病进展。在已建立肾小球损伤的小鼠中拯救足细胞mGPDH表达显著改善了它们的肾功能。总之，我们的研究表明，mGPDH的激活诱导线粒体生物合成和增强线粒体功能，这可能提供一个潜在的治疗靶点，以防止足细胞损伤和蛋白尿在糖尿病肾病。
Mitochondrial function is essential for bioenergetics, metabolism, and signaling and is compromised in diseases such as proteinuric kidney diseases, contributing to the global burden of kidney failure, cardiovascular morbidity, and death. The key cell type that prevents proteinuria is the terminally differentiated glomerular podocyte. In this study, we characterized the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated diabetes- or adriamycin-induced proteinuria, podocyte injury, and glomerular pathology. RNA sequencing revealed that mGPDH regulated the receptor for the advanced glycation end product (RAGE) signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased reactive oxygen species generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury significantly improved their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.