Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;
J Am Soc Nephrol. 2013 Nov;24(11):1769-81. doi: 10.1681/ASN.2012111080. Epub 2013 Oct 3.
Obesity is an independent risk factor for renal dysfunction in patients with CKDs, including diabetic nephropathy, but the mechanism underlying this connection remains unclear. Autophagy is an intracellular degradation system that maintains intracellular homeostasis by removing damaged proteins and organelles, and autophagy insufficiency is associated with the pathogenesis of obesity-related diseases. We therefore examined the role of autophagy in obesity-mediated exacerbation of proteinuria-induced proximal tubular epithelial cell damage in mice and in human renal biopsy specimens. In nonobese mice, overt proteinuria, induced by intraperitoneal free fatty acid-albumin overload, led to mild tubular damage and apoptosis, and activated autophagy in proximal tubules reabsorbing urinary albumin. In contrast, diet-induced obesity suppressed proteinuria-induced autophagy and exacerbated proteinuria-induced tubular cell damage. Proximal tubule-specific autophagy-deficient mice, resulting from an Atg5 gene deletion, subjected to intraperitoneal free fatty acid-albumin overload developed severe proteinuria-induced tubular damage, suggesting that proteinuria-induced autophagy is renoprotective. Mammalian target of rapamycin (mTOR), a potent suppressor of autophagy, was activated in proximal tubules of obese mice, and treatment with an mTOR inhibitor ameliorated obesity-mediated autophagy insufficiency. Furthermore, both mTOR hyperactivation and autophagy suppression were observed in tubular cells of specimens obtained from obese patients with proteinuria. Thus, in addition to enhancing the understanding of obesity-related cell vulnerability in the kidneys, these results suggest that restoring the renoprotective action of autophagy in proximal tubules may improve renal outcomes in obese patients.
肥胖是 CKD 患者（包括糖尿病肾病患者）肾功能障碍的独立危险因素，但这种关联的机制尚不清楚。自噬是一种细胞内降解系统，通过清除受损的蛋白质和细胞器来维持细胞内的平衡，而自噬不足与肥胖相关疾病的发病机制有关。因此，我们研究了自噬在肥胖介导的蛋白尿诱导的近端肾小管上皮细胞损伤中的作用，分别在小鼠和人类肾活检标本中进行了研究。在非肥胖小鼠中，腹腔内游离脂肪酸-白蛋白过载引起的明显蛋白尿导致轻度肾小管损伤和细胞凋亡，并激活了重吸收尿白蛋白的近端肾小管中的自噬。相比之下，饮食诱导的肥胖抑制了蛋白尿诱导的自噬，并加重了蛋白尿诱导的肾小管细胞损伤。由于 Atg5 基因缺失导致的近端小管特异性自噬缺陷小鼠，在接受腹腔内游离脂肪酸-白蛋白过载后，发生严重的蛋白尿诱导的肾小管损伤，表明蛋白尿诱导的自噬具有肾脏保护作用。雷帕霉素靶蛋白（mTOR）是自噬的强效抑制剂，在肥胖小鼠的近端小管中被激活，用 mTOR 抑制剂治疗可改善肥胖介导的自噬不足。此外，在肥胖伴蛋白尿患者的肾小管细胞中，均观察到 mTOR 过度激活和自噬抑制。因此，这些结果不仅加深了对肥胖相关肾脏细胞脆弱性的认识，还表明恢复近端肾小管的自噬保护作用可能改善肥胖患者的肾脏预后。
