Kawaoka Koichiro, Doi Shigehiro, Nakashima Ayumu, Yamada Kyoko, Ueno Toshinori, Doi Toshiki, Masaki Takao
Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
Department of Blood Purification, Hiroshima University Hospital, 1-2-3 Kasumi Minami-ku, Hiroshima, 734-8551, Japan.
Clin Exp Nephrol. 2017 Oct;21(5):771-780. doi: 10.1007/s10157-016-1365-6. Epub 2016 Dec 7.
Renal fibrosis is a common pathological feature of the progression of chronic kidney disease. Although valproic acid (VPA) has been recently shown to induce autophagy, the effect of VPA-induced autophagy on renal fibrosis remains unknown. We, therefore, investigated whether VPA-induced autophagy suppresses renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO).
Male C57BL/6 mice were divided into five groups (n = 8 per group): (1) sham group; (2) vehicle group; (3) VPA-treated group; (4) 3-methyladenine (3-MA; autophagy inhibitor)-treated group; and (5) VPA plus 3-MA-treated group. Mice underwent UUO and the kidneys were studied after 5 days. We also investigated the effect of VPA-induced autophagy on α-smooth muscle actin (α-SMA) in transforming growth factor (TGF)-β1-stimulated rat kidney fibroblasts and epithelial cells.
VPA attenuated renal fibrosis and induced autophagy in UUO mice, while 3-MA increased renal fibrosis and suppressed autophagy. In addition, the anti-fibrotic effect of VPA was diminished by 3-MA in UUO mice. In rat kidney fibroblasts and epithelial cells, VPA suppressed TGF-β1-stimulated α-SMA expression and induced autophagy. In contrast, 3-MA enhanced α-SMA expression while inhibiting autophagy. Furthermore, the combined use of VPA and 3-MA treatments increased the expression of α-SMA compared with VPA treatment alone in TGF-β1-stimulated rat kidney fibroblasts and epithelial cells, which was accompanied by the inhibition of autophagy.
These findings suggest that VPA may be a candidate drug for the treatment of renal fibrosis through the induction of autophagy.
肾纤维化是慢性肾脏病进展的常见病理特征。尽管最近研究表明丙戊酸（VPA）可诱导自噬，但VPA诱导的自噬对肾纤维化的影响仍不清楚。因此，我们研究了VPA诱导的自噬是否能在单侧输尿管梗阻（UUO）小鼠模型中抑制肾纤维化。
将雄性C57BL/6小鼠分为五组（每组n = 8）：（1）假手术组；（2）溶剂对照组；（3）VPA治疗组；（4）3-甲基腺嘌呤（3-MA；自噬抑制剂）治疗组；（5）VPA加3-MA治疗组。小鼠接受UUO手术，5天后对肾脏进行研究。我们还研究了VPA诱导的自噬对转化生长因子（TGF）-β1刺激的大鼠肾成纤维细胞和上皮细胞中α-平滑肌肌动蛋白（α-SMA）的影响。
VPA减轻了UUO小鼠的肾纤维化并诱导了自噬，而3-MA则加重了肾纤维化并抑制了自噬。此外，在UUO小鼠中，3-MA减弱了VPA的抗纤维化作用。在大鼠肾成纤维细胞和上皮细胞中，VPA抑制了TGF-β1刺激的α-SMA表达并诱导了自噬。相反，3-MA增强了α-SMA表达，同时抑制了自噬。此外，在TGF-β1刺激的大鼠肾成纤维细胞和上皮细胞中，与单独使用VPA治疗相比，联合使用VPA和3-MA治疗增加了α-SMA的表达，同时伴有自噬的抑制。
这些发现表明，VPA可能是一种通过诱导自噬来治疗肾纤维化的候选药物。
