Insulin signaling: implications for podocyte biology in diabetic kidney disease.
Insulin signaling: implications for podocyte biology in diabetic kidney disease.
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DOI：
10.1097/mnh.0000000000000078
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发表时间：
2015-01
影响因子：
3.2
通讯作者：
Fornoni A
中科院分区：
文献类型：
--
作者：
Coward R;Fornoni A
胰岛素信号级联的几个关键要素有助于足细胞的功能和存活。虽然最初认为改变的胰岛素信号传导对足细胞功能的后果与改变的葡萄糖摄取严格相关，但已经清楚的是，涉及细胞存活、脂质代谢或营养感测并由胰岛素调节的上游信号传导事件是足细胞功能的强独立贡献者。Akt 2是细胞胰岛素刺激后激活的Akt的主要亚型，可防止肾单位缺陷小鼠肾脏疾病的进展，并且足细胞特异性缺失Akt2可导致实验性肾小球疾病更快的进展。在糖尿病中，足细胞哺乳动物雷帕霉素靶激活明显有助于足细胞损伤和调节自噬。此外，足细胞特异性葡萄糖转运蛋白4型（GLUT4）缺陷通过阻止哺乳动物靶向雷帕霉素信号传导而保护足细胞，而不依赖于葡萄糖摄取。最后，细胞内脂质最近被认为是足细胞胰岛素信号转导的主要调节剂，并作为一个新的治疗靶点。对足细胞胰岛素信号传导的新贡献者的鉴定具有极端的转化价值，因为它可能导致糖尿病肾病以及其他蛋白尿肾病的新药开发策略。
Several key elements of the insulin signaling cascade contribute to podocyte function and survival. While it was initially thought that the consequences of altered insulin signaling to podocyte function was strictly related to altered glucose uptake, it has become clear that upstream signaling events involved in cell survival, lipid metabolism or nutrient sensing and modulated by insulin are strong independent contributors to podocyte function. Akt2, the major isoform of Akt activated following cellular insulin stimulation, protects against the progression of renal disease in nephron-deficient mice, and podocyte-specific deletion of Akt2 results in a more rapid progression of experimental glomerular disease. In diabetes, podocyte mammalian target of rapamycin activation clearly contributes to podocyte injury and regulated autophagy. Furthermore, podocyte-specific glucose transporter type 4 (GLUT4) deficiency protects podocytes by preventing mammalian target of rapamycin signaling independently of glucose uptake. Finally, intracellular lipids have been recently recognized as major modulators of podocyte insulin signaling and as a new therapeutic target. The identification of new contributors to podocyte insulin signaling is of extreme translational value as it may lead to new drug development strategies for diabetic kidney disease, as well as for other proteinuric kidney diseases.