Maeshima Akito, Mishima Keiichiro, Yamashita Shin, Nakasatomi Masao, Miya Masaaki, Sakurai Noriyuki, Sakairi Toru, Ikeuchi Hidekazu, Hiromura Keiju, Hasegawa Yoshihisa, Kojima Itaru, Nojima Yoshihisa
Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
School of Veterinary Medicine and Animal Science, Kitasato University, Towada 034-8628, Japan.
Biomed Res Int. 2014;2014:376191. doi: 10.1155/2014/376191. Epub 2014 May 5.
Activin, a member of the TGF-β superfamily, regulates cell growth and differentiation in various cell types. Activin A acts as a negative regulator of renal development as well as tubular regeneration after renal injury. However, it remains unknown whether activin A is involved in renal fibrosis. To clarify this issue, we utilized a rat model of unilateral ureteral obstruction (UUO). The expression of activin A was significantly increased in the UUO kidneys compared to that in contralateral kidneys. Activin A was detected in glomerular mesangial cells and interstitial fibroblasts in normal kidneys. In UUO kidneys, activin A was abundantly expressed by interstitial α-SMA-positive myofibroblasts. Administration of recombinant follistatin, an activin antagonist, reduced the fibrotic area in the UUO kidneys. The number of proliferating cells in the interstitium, but not in the tubules, was significantly lower in the follistatin-treated kidneys. Expression of α-SMA, deposition of type I collagen and fibronectin, and CD68-positive macrophage infiltration were significantly suppressed in the follistatin-treated kidneys. These data suggest that activin A produced by interstitial fibroblasts acts as a potent profibrotic factor during renal fibrosis. Blockade of activin A action may be a novel approach for the prevention of renal fibrosis progression.
激活素是转化生长因子-β超家族的成员之一，可调节多种细胞类型的细胞生长和分化。激活素A作为肾脏发育以及肾损伤后肾小管再生的负调节因子。然而，激活素A是否参与肾纤维化仍不清楚。为了阐明这个问题，我们使用了单侧输尿管梗阻（UUO）大鼠模型。与对侧肾脏相比，激活素A在UUO肾脏中的表达显著增加。在正常肾脏的肾小球系膜细胞和间质成纤维细胞中检测到激活素A。在UUO肾脏中，激活素A在间质α-SMA阳性肌成纤维细胞中大量表达。给予激活素拮抗剂重组卵泡抑素可减少UUO肾脏中的纤维化面积。在卵泡抑素处理的肾脏中，间质而非肾小管中增殖细胞的数量显著降低。卵泡抑素处理的肾脏中α-SMA的表达、I型胶原和纤连蛋白的沉积以及CD68阳性巨噬细胞浸润均显著受到抑制。这些数据表明，间质成纤维细胞产生的激活素A在肾纤维化过程中作为一种有效的促纤维化因子起作用。阻断激活素A的作用可能是预防肾纤维化进展的一种新方法。
