P2X7R/AKT/mTOR signaling mediates high glucose-induced decrease in podocyte autophagy.
P2X7R/AKT/mTOR signaling mediates high glucose-induced decrease in podocyte autophagy.
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DOI：
10.1016/j.freeradbiomed.2023.05.015
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发表时间：
2023-05
影响因子：
7.4
通讯作者：
Cheng Qian;Jiayue Lu;Xiajing Che;Lulin Min;Minzhou Wang;Ahui Song;R. Lu;L. Gu;K. Xie
中科院分区：
文献类型：
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作者：
Cheng Qian;Jiayue Lu;Xiajing Che;Lulin Min;Minzhou Wang;Ahui Song;R. Lu;L. Gu;K. Xie
糖尿病肾病是全世界终末期肾病的主要原因之一。在我们的研究中，我们发现糖尿病小鼠尿液中三磷酸腺苷（ATP）的含量显着增加。我们检查了肾皮质中所有嘌呤能受体的表达，发现野生型糖尿病小鼠肾皮质中只有嘌呤能P2X7受体（P2X7R）表达显着增加，并且P2X7R蛋白部分与足细胞共定位。与P2X7R(−/−)非糖尿病小鼠相比，P2X7R(−/−)糖尿病小鼠肾皮质中足细胞标记蛋白podocin稳定表达。野生型糖尿病小鼠肾脏中微管相关蛋白轻链3（LC-3II）的表达显着低于野生型对照，而P2X7R（−/−）糖尿病小鼠肾脏中LC-3II的表达与P2X7R（−/−）非糖尿病小鼠没有显着差异。在体外，高葡萄糖诱导足细胞中 p-Akt/Akt、p-mTOR/mTOR 和 p62 蛋白表达增加，同时 LC-3II 水平降低，而转染 P2X7R siRNA 后，磷酸化蛋白激酶 B (p-Akt)/Akt、磷酸化哺乳动物雷帕霉素靶点 (p-mTOR)/mTOR 和 p62 表达恢复，并且LC-3II 表达增加。此外，分别用 MK2206 和雷帕霉素抑制 Akt 和 mTOR 信号传导后，LC-3II 表达也得到恢复。我们的研究结果表明，糖尿病足细胞中 P2X7R 表达增加，并且 P2X7R 参与高糖对足细胞自噬的抑制，至少部分通过 Akt-mTOR 通路，从而加剧足细胞损伤，促进糖尿病肾病的发病。靶向 P2X7R 可能是糖尿病肾病的潜在治疗方法。
Diabetic nephropathy is one of the leading causes of end-stage renal disease worldwide. In our study we found that Adenosine triphosphate (ATP) content was significantly increased in the urine of diabetic mice. We examined the expression of all purinergic receptors in the renal cortex and found that only purinergic P2X7 receptor (P2X7R) expression was significantly increased in the renal cortex of wild-type diabetic mice and that the P2X7R protein partially co-localized with podocytes. Compared with P2X7R(−/−) non-diabetic mice, P2X7R(−/−) diabetic mice showed stable expression of the podocyte marker protein podocin in the renal cortex. The renal expression of microtubule associated protein light chain 3 (LC-3II) in wild-type diabetic mice was significantly lower than in wild-type controls, whereas the expression of LC-3II in the kidneys of P2X7R(−/−) diabetic mice was not significantly different from that of P2X7R(−/−) non-diabetic mice. In vitro, high glucose induced an increase in p-Akt/Akt, p-mTOR/mTOR and p62 protein expression along with a decrease in LC-3II levels in podocytes, whereas after transfection with P2X7R siRNA, Phosphorylated protein kinase B (p-Akt)/Akt, Phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR, and p62 expression were restored and LC-3II expression was increased. In addition, LC-3II expression was also restored after inhibition of Akt and mTOR signaling with MK2206 and rapamycin, respectively. Our results suggest that P2X7R expression is increased in podocytes in diabetes, and that P2X7R is involved in the inhibition of podocyte autophagy by high glucose, at least in part through the Akt-mTOR pathway, thereby exacerbating podocyte damage and promoting the onset of diabetic nephropathy. Targeting P2X7R may be a potential treatment for diabetic nephropathy.