Induction of heme oxygenase-1 modulates the profibrotic effects of transforming growth factor-beta in human renal tubular epithelial cells
Induction of heme oxygenase-1 modulates the profibrotic effects of transforming growth factor-beta in human renal tubular epithelial cells
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DOI：
10.1170/t638
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发表时间：
2005-01-01
影响因子：
1.6
通讯作者：
Hill-Kapturczak, N
中科院分区：
文献类型：
--
作者：
Mark, A;Hock, T;Hill-Kapturczak, N
转化生长因子- β (tgf - β)与多种肾脏疾病有关，它促进细胞外基质（ECM）沉积和促炎事件，但它也通过激活细胞保护蛋白（包括血红素加氧酶-1 (HO-1)）来稳定和减轻组织损伤。HO-1催化血红素转化为一氧化碳、铁和胆绿素，胆绿素随后转化为胆红素。HO-1诱导的有益作用包括减少促氧化剂（血红素），增加抗氧化剂（胆绿素和胆红素），并产生具有抗凋亡和抗炎特性的血管扩张剂（CO）。HO-1的反应产物也可能具有抗纤维化的特性。本研究的目的是探讨HO-1表达及其反应产物对肾脏ECM蛋白纤维连接蛋白的影响。结果表明，HO-1基因敲除小鼠的肾脏比杂合子小鼠表达更多的纤维连接蛋白。HO-1的一种强效诱导剂血红蛋白显著降低纤维连接蛋白，同时HO-1蛋白升高。通过tgf - β 1诱导表达HO-1的细胞减少了纤维连接蛋白的表达。胆红素是血红素加氧酶反应的产物，可减弱tgf - β 1介导的纤维连接蛋白表达的增加。这些结果表明，HO-1的诱导和活性可能调节ECM成分的产生，并提示tgf - β介导的HO-1诱导在减轻肾纤维化中的潜在作用。
Transforming growth factor-beta (TGF-beta) is implicated in a variety of kidney diseases where it promotes extracellular matrix (ECM) deposition and pro-inflammatory events, but it also stabilizes and attenuates tissue injury through the activation of cytoprotective proteins, including heme oxygenase-1 (HO-1). HO-1 catalyzes the conversion of heme into carbon monoxide (CO), iron, and biliverdin, which is subsequently converted to bilirubin. The beneficial effects of HO-1 induction include decreasing pro-oxidants (heme), increasing anti-oxidants (biliverdin and bilirubin), and producing a vasodilator with anti-apoptotic and anti-inflammatory properties (CO). The reaction products of HO-1 may also have antifibrogenic properties. The purpose of this study is to explore the effects of HO-1 expression and its reaction products on fibronectin, an ECM protein, in the kidney. The results demonstrate that kidneys of HO-1 knockout mice express significantly more fibronectin protein as compared to heterozygote mice. A potent inducer of HO-1, hemin, significantly decreases fibronectin protein with a concomitant increase in HO-1 protein. Cells expressing HO-1, via TGF-beta1 induction, have reduced fibronectin expression. Bilirubin, a product of the heme oxygenase reaction, attenuates TGF-beta1-mediated increases in fibronectin expression. These results indicate that HO-1 induction and activity may modulate the production of ECM components and suggest a potential role for TGF-beta-mediated HO-1 induction in attenuating renal fibrosis.