Impaired Podocyte Autophagy Exacerbates Proteinuria in Diabetic Nephropathy

Atsuko Tagawa, Mako Yasuda, Shinji Kume, Kosuke Yamahara, Jun Nakazawa, Masami Chin-Kanasaki, Hisazumi Araki, Shin-Ichi Araki, Daisuke Koya, Katsuhiko Asanuma, Eun-Hee Kim, Masakazu Haneda, Nobuyuki Kajiwara, Kazuyuki Hayashi, Hiroshi Ohashi, Satoshi Ugi, Hiroshi Maegawa, Takashi Uzu
Diabetes 2016, 65 (3): 755-67
Overcoming refractory massive proteinuria remains a clinical and research issue in diabetic nephropathy. This study was designed to investigate the pathogenesis of massive proteinuria in diabetic nephropathy, with a special focus on podocyte autophagy, a system of intracellular degradation that maintains cell and organelle homeostasis, using human tissue samples and animal models. Insufficient podocyte autophagy was observed histologically in patients and rats with diabetes and massive proteinuria accompanied by podocyte loss, but not in those with no or minimal proteinuria. Podocyte-specific autophagy-deficient mice developed podocyte loss and massive proteinuria in a high-fat diet (HFD)-induced diabetic model for inducing minimal proteinuria. Interestingly, huge damaged lysosomes were found in the podocytes of diabetic rats with massive proteinuria and HFD-fed, podocyte-specific autophagy-deficient mice. Furthermore, stimulation of cultured podocytes with sera from patients and rats with diabetes and massive proteinuria impaired autophagy, resulting in lysosome dysfunction and apoptosis. These results suggest that autophagy plays a pivotal role in maintaining lysosome homeostasis in podocytes under diabetic conditions, and that its impairment is involved in the pathogenesis of podocyte loss, leading to massive proteinuria in diabetic nephropathy. These results may contribute to the development of a new therapeutic strategy for advanced diabetic nephropathy.

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