Department of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
Kidney Int. 2012 Mar;81(5):449-57. doi: 10.1038/ki.2011.403. Epub 2011 Dec 7.
Unilateral ureteral obstruction is a well-established experimental model of progressive renal fibrosis. We tested whether mechanical stretch and subsequent renal tubular distension might lead to renal fibrosis by first studying renal tubular epithelial cells in culture. We found that mechanical stretch induced reactive oxygen species that in turn activated the cytoplasmic proline-rich tyrosine kinase-2 (Pyk2). This kinase is abundantly expressed in tubular epithelial cells where it is activated by several stimuli. Using mice with deletion of Pyk2 we found that the expression of transforming growth factor-β1 induced by mechanical stretch in renal tubular epithelial cells was significantly reduced. The expression of connective tissue growth factor was also reduced in the Pyk2(-/-) mice. We also found that expression of connective tissue growth factor was independent of transforming growth factor-β1, but dependent on the Rho-associated coiled-coil forming protein kinase pathway. Thus, Pyk2 may be an important initiating factor in renal fibrosis and might be a new therapeutic target for ameliorating renal fibrosis.
单侧输尿管梗阻是一种成熟的进行性肾纤维化实验模型。我们首先研究了培养的肾小管上皮细胞，以检验机械拉伸及其随后导致的肾小管扩张是否会引发肾纤维化。我们发现机械拉伸会诱发活性氧，进而激活富含脯氨酸的酪氨酸激酶-2（Pyk2）。这种激酶在肾小管上皮细胞中大量表达，并且可被多种刺激激活。利用 Pyk2 缺失的小鼠，我们发现机械拉伸诱导的肾小管上皮细胞中转化生长因子-β1 的表达明显减少。结缔组织生长因子的表达在 Pyk2（-/-）小鼠中也降低了。我们还发现结缔组织生长因子的表达不依赖于转化生长因子-β1，但依赖于 Rho 相关卷曲螺旋形成蛋白激酶途径。因此，Pyk2 可能是肾纤维化的一个重要起始因子，并且可能成为改善肾纤维化的新治疗靶点。
