Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Región de los Ríos, Valdivia, Chile.
J Cell Biochem. 2013 Mar;114(3):639-49. doi: 10.1002/jcb.24406.
Diabetes is the major cause of end stage renal disease, and tubular alterations are now considered to participate in the development and progression of diabetic nephropathy (DN). Here, we report for the first time that expression of the insulin receptor (IR) in human kidney is altered during diabetes. We detected a strong expression in proximal and distal tubules from human renal cortex, and a significant reduction in type 2 diabetic patients. Moreover, isolated proximal tubules from type 1 diabetic rat kidney showed a similar response, supporting its use as an excellent model for in vitro study of human DN. IR protein down-regulation was paralleled in proximal and distal tubules from diabetic rats, but prominent in proximal tubules from diabetic patients. A target of renal insulin signaling, the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK), showed increased expression and activity, and localization in compartments near the apical membrane of proximal tubules, which was correlated with activation of the GSK3β kinase in this specific renal structure in the diabetic condition. Thus, expression of IR protein in proximal tubules from type 1 and type 2 diabetic kidney indicates that this is a common regulatory mechanism which is altered in DN, triggering enhanced gluconeogenesis regardless the etiology of the disease.
糖尿病是终末期肾病的主要病因，目前认为肾小管改变参与了糖尿病肾病（DN）的发生和发展。在这里，我们首次报道在糖尿病过程中，人肾脏中的胰岛素受体（IR）表达发生改变。我们在人肾皮质的近端和远端小管中检测到强烈的表达，而在 2 型糖尿病患者中则显著减少。此外，1 型糖尿病大鼠肾脏分离的近端小管也表现出类似的反应，支持其作为体外研究人类 DN 的理想模型。IR 蛋白在糖尿病大鼠的近端和远端小管中下调，但在糖尿病患者的近端小管中更为明显。肾脏胰岛素信号的一个靶标，糖异生酶磷酸烯醇丙酮酸羧激酶（PEPCK），在近端小管中的表达和活性增加，并定位于靠近近端小管顶膜的隔室，这与在糖尿病状态下该特定肾脏结构中 GSK3β激酶的激活相关。因此，1 型和 2 型糖尿病肾脏的近端小管中 IR 蛋白的表达表明，这是一种共同的调节机制，在 DN 中发生改变，触发增强的糖异生，而与疾病的病因无关。
