Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells
Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells
复制标题
DOI：
10.1152/ajprenal.00422.2018
复制
发表时间：
2019-06-01
影响因子：
4.2
通讯作者：
Dong, Zheng
中科院分区：
文献类型：
--
作者：
Wei, Qingqing;Su, Jennifer;Dong, Zheng
肾间质纤维化是慢性肾脏疾病的常见病理特征，其可能涉及肾细胞的代谢改变。在本研究中，我们首先表明，阻断糖酵解与二氯醋酸酯（DCA）或紫草素靶向不同的糖酵解酶减少肾纤维化的小鼠模型单侧输尿管梗阻（UUO）。这两种抑制剂明显抑制了梗阻肾脏中纤连蛋白和I型胶原的诱导，DCA还显示出对IV型胶原和α-平滑肌肌动蛋白（α-SMA）的抑制作用。组织学检查也证实了DCA治疗的肾脏中胶原沉积较少。DCA和紫草素均能显著抑制UUO大鼠肾小管细胞凋亡，但对间质细胞凋亡无明显影响。UUO损伤后巨噬细胞浸润也受到抑制。紫草素，而不是DCA，引起明显的动物体重减轻在UUO。为了确定紫草素和DCA是否对肾小管细胞和/或成纤维细胞起作用，我们在缺氧或转化生长因子-β（1）处理期间测试了它们对培养的肾近端肾小管BUMPT细胞和肾NRK-49 F成纤维细胞的作用。尽管这两种抑制剂在缺氧或转化生长因子-β（1）处理期间减少NRK-49 F细胞中纤连蛋白和α-SMA的产生，但它们不抑制BUMPT细胞中纤连蛋白和α-SMA的表达。总之，这些结果证明了糖酵解抑制剂对肾间质纤维化的抑制作用。在这方面DCA对纤维化的抑制作用强于紫草素，对动物的毒性也较紫草素小。
Renal interstitial fibrosis is a common pathological feature of chronic kidney disease that may involve changes of metabolism in kidney cells. In the present study, we first showed that blockade of glycolysis with either dichloroacetate (DCA) or shikonin to target different glycolytic enzymes reduced renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). Both inhibitors evidently suppressed the induction of fibronectin and collagen type I in obstructed kidneys, with DCA also showing inhibitory effects on collagen type IV and alpha-smooth muscle actin (alpha-SMA). Histological examination also confirmed less collagen deposition in DCA-treated kidneys. Both DCA and shikonin significantly inhibited renal tubular apoptosis but not interstitial apoptosis in UUO. Macrophage infiltration after UUO injury was also suppressed. Shikonin, but not DCA, caused obvious animal weight loss during UUO. To determine whether shikonin and DCA worked on tubular cells and/or fibroblasts, we tested their effects on cultured renal proximal tubular BUMPT cells and renal NRK-49F fibroblasts during hypoxia or transforming growth factor-beta(1) treatment. Although both inhibitors reduced fibronectin and alpha-SMA production in NRK-49F cells during hypoxia or transforming growth factor-beta(1) treatment, they did not suppress fibronectin and alpha-SMA expression in BUMPT cells. Altogether, these results demonstrate the inhibitory effect of glycolysis inhibitors on renal interstitial fibrosis. In this regard. DCA is more potent for fibrosis inhibition and less toxic to animals than shikonin.