Obesity-Mediated Autophagy Insufficiency Exacerbates Proteinuria-induced Tubulointerstitial Lesions

作者：Kosuke Yamahara, Shinji Kume, Daisuke Koya, Yuki Tanaka, Yoshikata Morita, Masami Chin‒Kanasaki, Hisazumi Araki, Keiji Isshiki, Shin‐ichi Araki, Masakazu Haneda, Taiji Matsusaka, Atsunori Kashiwagi, Hiroshi Maegawa, Takashi Uzu · 发表于：Journal of the American Society of Nephrology · 年份：2013 · DOI：10.1681/asn.2012111080 · 被引用次数：215 · 研究领域：Autophagy in Disease and Therapy、Chronic Kidney Disease and Diabetes、Cannabis and Cannabinoid Research

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 tu...