Hypoxia inducible factor-1α mediates the profibrotic effect of albumin in renal tubular cells.
Hypoxia inducible factor-1α mediates the profibrotic effect of albumin in renal tubular cells.
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DOI：
10.1038/s41598-017-15972-8
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发表时间：
2017-11-20
影响因子：
4.6
通讯作者：
Li N
中科院分区：
文献类型：
--
作者：
Hu J;Wang W;Zhang F;Li PL;Boini KM;Yi F;Li N
蛋白尿通过引起肾小管间质纤维化而与慢性肾脏疾病（CKD）的进展密切相关。缺氧诱导因子（HIF）-1α的过度激活与CKD的进展有关。本研究验证了HIF-1α介导白蛋白诱导的近端肾小管细胞促纤维化作用的假设。白蛋白（40 μg/ml）孵育72 h后，HIF-1α、TIMP-1和I型胶原蛋白水平显著升高，但HIF-1α shRNA可阻断上述作用。白蛋白还刺激了上皮-间质转化（EMT），如上皮标志物E-钙粘蛋白减少和间质标志物α-平滑肌肌动蛋白和成纤维细胞特异性蛋白1增加所示。HIF-1α shRNA也阻断了白蛋白诱导的这些EMT标志物的变化。此外，白蛋白降低了羟基化HIF-1α的水平，表明抑制了脯氨酰羟化酶（促进HIF-1α降解的酶）的活性。抗氧化剂抗坏血酸逆转白蛋白诱导的脯氨酰羟化酶活性抑制。过表达脯氨酰羟化酶2（PHD 2）转基因（肾小管中PHDs的主要亚型）以降低HIF-1α水平可显著减弱白蛋白诱导的TIMP-1和胶原-I水平的升高。这些结果表明，白蛋白诱导的氧化应激抑制PHD活性，以积累HIF-1α，介导白蛋白诱导的促肾小管细胞纤维化作用。
Proteinuria is closely associated with the progression of chronic kidney diseases (CKD) by producing renal tubulointerstitial fibrosis. Over-activation of hypoxia inducible factor (HIF)-1α has been implicated in the progression of CKD. The present study tested the hypothesis that HIF-1α mediates albumin-induced profibrotic effect in cultured renal proximal tubular cells. Incubation of the cells with albumin (40 μg/ml) for 72 hrs significantly increased the protein levels of HIF-1α, tissue inhibitor of metalloproteinase (TIMP)-1 and collagen-I, which were blocked by HIF-1α shRNA. Albumin also stimulated an epithelial-mesenchymal transition (EMT) as indicated by the decrease in epithelial marker E-cadherin, and the increase in mesenchymal markers α-smooth muscle actin and fibroblast-specific protein 1. HIF-1α shRNA blocked albumin-induced changes in these EMT markers as well. Furthermore, albumin reduced the level of hydroxylated HIF-1α, indicating an inhibition of the activity of prolyl-hydroxylases, enzymes promoting the degradation of HIF-1α. An anti-oxidant ascorbate reversed albumin-induced inhibition of prolyl-hydroxylase activity. Overexpression of prolyl-hydroxylase 2 (PHD2) transgene, a predominant isoform of PHDs in renal tubules, to reduce HIF-1α level significantly attenuated albumin-induced increases in TIMP-1 and collagen-I levels. These results suggest that albumin-induced oxidative stress inhibits PHD activity to accumulate HIF-1α, which mediates albumin-induced profibrotic effects in renal tubular cells.
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DOI：
10.1016/j.bbamcr.2013.02.029
发表时间：
2013-06
影响因子：
5.1
作者：
Han, Wei-Qing;Zhu, Qing;Hu, Junping;Li, Pin-Lan;Zhang, Fan;Li, Ningjun
通讯作者：
Li, Ningjun
影响因子：
4.3
作者：
Higgins, Debra F.;Kimura, Kuniko;Haase, Volker H.
通讯作者：
Haase, Volker H.
影响因子：
3.7
作者：
Callapina, M;Zhou, J;Brüne, B
通讯作者：
Brüne, B
影响因子：
4.2
作者：
Hills, Claire E.;Squires, Paul E.
通讯作者：
Squires, Paul E.
影响因子：
56.9
作者：
Bruick, RK;McKnight, SL
通讯作者：
McKnight, SL