Wnt/β-catenin signaling modulates survival of high glucose-stressed mesangial cells
Wnt/β-catenin signaling modulates survival of high glucose-stressed mesangial cells
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DOI：
10.1681/asn.2005121355
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发表时间：
2006-10-01
影响因子：
13.6
通讯作者：
Wang, Feng-Sheng
中科院分区：
文献类型：
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作者：
Lin, Chun-Liang;Wang, Jeng-Yi;Wang, Feng-Sheng
肾小球硬化和糖尿病肾病与高糖诱导系膜细胞凋亡有关。虽然Wnt信号已被发现调节肾脏的形态发生和发病机制，但Wnt/β-catenin信号在控制高糖诱导的系膜细胞凋亡中的生物学作用尚不清楚。本研究报道Wnt/β-catenin信号通路对高糖诱导的肾小球系膜细胞凋亡具有保护作用。高糖可下调肾小球系膜细胞WNT4和WNT5a的表达及随后的β-连环蛋白的核转位，而增加肾小球系膜细胞糖原合成酶-3β(GSK-30)和半胱氨酸天冬氨酸氨基转移酶-3(caspase-3)的活性及细胞凋亡。Wnt4或Wnt5a或稳定的0-catenin(S33Y)可抑制GSK-30的激活或核内β-catenin的增加，逆转Akt的激活，减少高糖介导的caspase-3的裂解和细胞的凋亡。用重组Wnt5a、溴化吲哚红-3‘-肟或LiCl药理抑制GSK-3β，可增加Akt的磷酸化和β-连环蛋白的易位，并抑制高糖介导的促凋亡活性。外源性溴化朱红-3‘-肟治疗可降低糖尿病大鼠肾小球周围细胞的磷酸化丝氨酸-GSK-3β和β-连环蛋白表达及细胞凋亡，减少尿蛋白分泌。综上所述，系膜细胞对高糖的反应是通过破坏规范的写入途径来增加促凋亡活性。维持Wnt/β-catenin信号通路有利于促进高糖应激肾小球系膜细胞的存活。
Glomerulosclerosis and diabetic nephropathy are attributable to high glucose induction of mesangial cell apoptosis. Whereas Wnt signaling has been found to regulate renal morphogenesis and pathogenesis, the biologic role of Wnt/beta-catenin signaling in controlling high glucose-induced mesangial cell apoptosis is not well defined. Herein is reported that Wnt/beta-catenin signaling is required for protecting glomerular mesangial cells from high glucose-mediated cell apoptosis. High glucose downregulated Wnt4 and Wnt5a expression and the subsequent nuclear translocation of beta-catenin, whereas it increased glycogen synthase kinase-3 beta (GSK-30) and caspase-3 activities and apoptosis of glomerular mesangial cells. Suppression of GSK-30 activation or increase in nuclear beta-catenin by transfection of Wnt4 or Wnt5a or stable 0-catenin (S33Y) reversed Akt activation and reduced the high glucose-mediated caspase-3 cleavage and cell apoptosis. Pharmacologic inhibition of GSK-3 beta by recombinant Wnt5a or bromoindirubin-3'-oxime or LiCl increased Akt phosphorylation and beta-catenin translocation and abrogated high glucose-mediated proapoptotic activities. Exogenous bromoindirubin-3'-oxime treatment reduced phosphoSer'-GSK-3 beta and beta-catenin expression and apoptosis of cells adjacent to glomeruli in diabetic kidneys and attenuated urinary protein secretion in diabetic rats. Taken together, mesangial cells responded to high glucose by impairing that canonical Writ pathway to increase proapoptotic activities. Sustaining Wnt/beta-catenin signaling is beneficial for promoting survival of mesangial cells that are exposed to high glucose stress.