Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction.
Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction.
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DOI：
10.14814/phy2.12054
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发表时间：
2014-06-01
影响因子：
2.5
通讯作者：
Makino H
中科院分区：
文献类型：
--
作者：
Watatani H;Maeshima Y;Hinamoto N;Yamasaki H;Ujike H;Tanabe K;Sugiyama H;Otsuka F;Sato Y;Makino H
肾小管间质损伤可以预测慢性肾脏疾病(CKD)患者肾功能的恶化。我们最近报道了血管生成的负反馈调节因子Vasohibin-1(VASH-1)在糖尿病肾病中的保护作用，但其对肾小管间质损伤的影响尚不清楚。本研究旨在探讨内源性血管紧张素转换酶-1(VASH-1)对单侧输尿管梗阻(UUO)所致肾小管间质改变的调节作用，并探讨其在肾成纤维细胞纤维化形成及Smad3信号通路激活中的作用。在雌性Vasohibin-1杂合基因敲除小鼠(Vash-1+/−)或野生型(WT)(Vash-1+/+)小鼠中诱导UUO。左侧输尿管结扎后第7天处死小鼠，取肾组织。与WT小鼠(第7天)相比，VASH-1+/−小鼠梗阻肾(OBK)间质纤维化、I、III型胶原堆积及单核/巨噬细胞浸润明显加重。肾组织中转化生长因子-β-1、pSmad3、核因子-κ-Bpp65、CCL2m RNA水平及间质成纤维细胞特异性蛋白-1(FSP-1)+成纤维细胞数量的增加在VASH-1+/−小鼠中显著加重。此外，在体外，VASH-1siRNA可增强转化生长因子-β1诱导的成纤维细胞Smad3的磷酸化、Smad3途径的转录激活和I型/III型胶原的产生。综上所述，我们的研究结果表明，内源性血管紧张素转换酶-1通过调节炎症和纤维化对肾小管间质改变起到保护作用，并通过调节转化生长因子-β-1信号转导通路对肾成纤维细胞有直接的抗纤维化作用。本研究旨在探讨内源性Vasohibn-1 VASH-1对单侧输尿管梗阻(UUO)所致肾小管间质改变的调节作用，并探讨其在肾成纤维细胞纤维化形成及转化生长因子-β/Smad3信号通路激活中的作用。这是首次证实内源性血管紧张素转换酶-1通过调节炎症和纤维化对肾小管间质改变的潜在保护作用，部分是通过调节转化生长因子-β-1信号转导对肾成纤维细胞的直接抗纤维化作用。
Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease (CKD). We recently reported the protective role of Vasohibin‐1(VASH‐1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH‐1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin‐1 heterozygous knockout mice (VASH‐1+/−) or wild‐type (WT) (VASH‐1+/+) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys (OBK) were significantly exacerbated in VASH‐1+/− mice compared with WT mice (Day 7). The increases in the renal levels of TGF‐β1, pSmad3, NF‐κB pp65, CCL2 mRNA, and the number of interstitial fibroblast‐specific protein‐1 (FSP‐1)+ fibroblasts in the OBK were significantly aggravated in VASH‐1+/− mice. In addition, treatment with VASH‐1 siRNA enhanced the TGF‐β1‐induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH‐1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti‐fibrotic effects of VASH‐1 on renal fibroblasts through its modulation of TGF‐β1 signaling. In the present study, we evaluated the role of endogenous Vasohibn‐1 VASH‐1 in regulating tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO), and assessed its regulatory role on fibrogenesis and the activation of TGF‐beta/Smad3 signaling in renal fibroblasts. This is the first study to demonstrate the potential protective role for endogenous VASH‐1 on tubulointerstitial alterations via regulating inflammation and fibrosis, partly mediated via its direct anti‐fibrotic effects on renal fibroblasts through modulating TGF‐β1 signaling.