Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan;
J Am Soc Nephrol. 2019 Jun;30(6):929-945. doi: 10.1681/ASN.2018100983. Epub 2019 Apr 30.
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.
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.
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.
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.
自噬在肾脏疾病中具有保护作用的证据引起了人们对自噬作为一种潜在治疗策略的兴趣。然而，了解自噬过程在每种疾病中的变化对于朝着治疗应用的方向努力至关重要。
使用培养的肾脏近端肾小管上皮细胞 (PTEC) 和糖尿病小鼠模型，我们研究了 1 型与 2 型糖尿病肾病中自噬活性的差异。我们探讨了营养信号如何调节 PTEC 中的饥饿诱导自噬，并使用自噬监测小鼠和 PTEC 特异性自噬缺陷敲除小鼠来检查自噬状态的差异以及自噬在 STZ 治疗的 1 型和 / 2 型糖尿病肾病中 PTEC 中的作用。我们还检查了雷帕霉素（哺乳动物雷帕霉素靶蛋白 [mTOR] 的抑制剂）对缺血再灌注损伤易感性的影响。
给予胰岛素或氨基酸而不是葡萄糖会通过激活 mTOR 信号来抑制自噬。在 / 小鼠中，即使在饥饿状态下，自噬诱导也受到抑制；在 STZ 处理的小鼠中，自噬在喂食条件下增强，但由于溶酶体应激而在饥饿状态下停滞。使用患有糖尿病的基因敲除小鼠，我们发现，在 STZ 处理的小鼠中，激活的自噬可抵消肾脏中的线粒体损伤和纤维化，而在 / 小鼠中，即使在自噬功能正常的情况下，自噬抑制也会危及肾脏。雷帕霉素诱导的药理学自噬对 STZ 处理的和 / 小鼠的缺血再灌注损伤产生了相反的影响。
PTEC 中的自噬活性主要由胰岛素调节。因此，1 型和 2 型糖尿病肾病中的自噬活性不同，在通过调节自噬来开发治疗糖尿病肾病的策略时应考虑这一点。
