Department of Cellular and Structural Biology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
J Am Soc Nephrol. 2012 Oct;23(10):1652-62. doi: 10.1681/ASN.2012030285. Epub 2012 Aug 16.
Exposure of proximal tubular epithelial cells to high glucose contributes to the accumulation of tubulointerstitial and matrix proteins in diabetic nephropathy, but how this occurs is not well understood. We investigated the effect of the signaling molecule tuberin, which modulates the mammalian target of rapamycin pathway, on renal hypertrophy and fibronectin expression. We found that the kidney mass was significantly greater in partially tuberin-deficient (TSC2(+/-) ) diabetic rats than wild-type diabetic rats. Furthermore, TSC2(+/-) rats exhibited significant increases in the basal levels of phospho-tuberin and fibronectin expression in the kidney cortex. Increased levels of phosphorylated tuberin associated with an increase in fibronectin expression in both wild-type and TSC2(+/-) diabetic rats. Treatment with insulin abrogated the diabetes-induced increase in fibronectin expression. In vitro, high glucose enhanced fibronectin expression in TSC2(+/-) primary proximal tubular epithelial cells; both inhibition of Akt and inhibition of the mammalian target of rapamycin could prevent this effect of glucose. In addition, forced expression of tuberin in tuberin-null cells abolished the expression of fibronectin protein. Taken together, these data suggest that tuberin plays a central role in the development of renal hypertrophy and in modulating the production of the matrix protein fibronectin in diabetes.
高血糖使近端肾小管上皮细胞暴露，导致糖尿病肾病中肾小管间质和基质蛋白的积累，但具体机制尚不清楚。本研究探讨了信号分子雷帕霉素靶蛋白（mTOR）途径调节因子 tuberin 对肾脏肥大和纤维连接蛋白表达的影响。结果发现，部分 tuberin 缺陷（TSC2(+/-)）糖尿病大鼠的肾脏质量明显大于野生型糖尿病大鼠。此外，TSC2(+/-)大鼠肾脏皮质中磷酸化 tuberin 和纤维连接蛋白表达的基础水平显著增加。在野生型和 TSC2(+/-)糖尿病大鼠中，磷酸化 tuberin 水平的增加与纤维连接蛋白表达的增加相关。胰岛素治疗可消除糖尿病引起的纤维连接蛋白表达增加。在体外，高葡萄糖增强 TSC2(+/-)原代近端肾小管上皮细胞中纤维连接蛋白的表达；Akt 抑制和 mTOR 抑制均可阻止葡萄糖的这种作用。此外，tuberin 在 tuberin 缺失细胞中的强制表达可消除纤维连接蛋白蛋白的表达。综上所述，这些数据表明 tuberin 在肾脏肥大的发展和调节糖尿病中基质蛋白纤维连接蛋白的产生中起核心作用。
