Proximal Tubule Autophagy Differs in Type 1 and 2 Diabetes.
Sakai Shinsuke,Yamamoto Takeshi,Takabatake Yoshitsugu,Takahashi Atsushi,Namba-Hamano Tomoko,Minami Satoshi,Fujimura Ryuta,Yonishi Hiroaki,Matsuda Jun,Hesaka Atsushi,Matsui Isao,Matsusaka Taiji,Niimura Fumio,Yanagita Motoko,Isaka Yoshitaka
Journal of the American Society of Nephrology : JASN
BACKGROUND:Evidence of a protective role of autophagy in kidney diseases has sparked interest in autophagy as a potential therapeutic strategy. However, understanding how the autophagic process is altered in each disorder is critically important in working toward therapeutic applications. METHODS:Using cultured kidney proximal tubule epithelial cells (PTECs) and diabetic mouse models, we investigated how autophagic activity differs in type 1 versus type 2 diabetic nephropathy. We explored nutrient signals regulating starvation-induced autophagy in PTECs and used autophagy-monitoring mice and PTEC-specific autophagy-deficient knockout mice to examine differences in autophagy status and autophagy's role in PTECs in streptozotocin (STZ)-treated type 1 and / type 2 diabetic nephropathy. We also examined the effects of rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]) on vulnerability to ischemia-reperfusion injury. RESULTS:Administering insulin or amino acids, but not glucose, suppressed autophagy by activating mTOR signaling. In / mice, autophagy induction was suppressed even under starvation; in STZ-treated mice, autophagy was enhanced even under fed conditions but stagnated under starvation due to lysosomal stress. Using knockout mice with diabetes, we found that, in STZ-treated mice, activated autophagy counteracts mitochondrial damage and fibrosis in the kidneys, whereas in / mice, autophagic suppression jeopardizes kidney even in the autophagy-competent state. Rapamycin-induced pharmacologic autophagy produced opposite effects on ischemia-reperfusion injury in STZ-treated and mice. CONCLUSIONS:Autophagic activity in PTECs is mainly regulated by insulin. Consequently, autophagic activity differs in types 1 and 2 diabetic nephropathy, which should be considered when developing strategies to treat diabetic nephropathy by modulating autophagy.