Nakagawa Shunsaku, Masuda Satohiro, Nishihara Kumiko, Inui Ken-Ichi
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Biochem Pharmacol. 2010 Jan 1;79(1):67-76. doi: 10.1016/j.bcp.2009.07.015. Epub 2009 Aug 4.
Responsible factors in progressive tubular dysfunction in chronic renal failure have not been fully identified. In the present study, we hypothesized that the mammalian target of rapamycin, mTOR, was a key molecule in the degenerative and progressive tubular damage in chronic renal failure. Everolimus, an mTOR inhibitor, was administered for 14 days in 5/6 nephrectomized (Nx) rats at 2 and 8 weeks after renal ablation. Marked activation of the mTOR pathway was found at glomeruli and proximal tubules in remnant kidneys of Nx rats. The reduced expression levels of the phosphorylated S6 indicated the satisfactory pharmacological effects of treatment with everolimus for 14 days. Everolimus suppressed the accumulation of smooth muscle alpha actin, infiltration of macrophages and expression of kidney injury molecule-1 in the proximal tubules. In addition, everolimus-treatment restored the tubular reabsorption of albumin, and had a restorative effect on the expression levels of membrane transporters in the polarized proximal tubular epithelium, when its administration was started at 8 weeks after Nx. These results indicate that the constitutively activated mTOR pathway in proximal tubules has an important role in the progressive tubular dysfunction, and that mTOR inhibitors have renoprotective effects to improve the proximal tubular functions in end-stage renal disease.
慢性肾衰竭进行性肾小管功能障碍的相关因素尚未完全明确。在本研究中，我们假设雷帕霉素靶蛋白（mTOR）是慢性肾衰竭肾小管退变和进行性损伤的关键分子。在肾切除术后2周和8周，对5/6肾切除（Nx）大鼠给予mTOR抑制剂依维莫司，持续给药14天。在Nx大鼠残余肾脏的肾小球和近端小管中发现mTOR通路明显激活。磷酸化S6表达水平降低表明依维莫司治疗14天具有良好的药理作用。依维莫司抑制了近端小管中平滑肌α肌动蛋白的积累、巨噬细胞浸润以及肾损伤分子-1的表达。此外，当在Nx术后8周开始给予依维莫司时，其治疗可恢复肾小管对白蛋白的重吸收，并对极化近端小管上皮细胞膜转运蛋白的表达水平具有恢复作用。这些结果表明，近端小管中持续激活的mTOR通路在进行性肾小管功能障碍中起重要作用，并且mTOR抑制剂具有肾脏保护作用，可改善终末期肾病中的近端小管功能。
