Interactions of transforming growth factor-β and angiotensin II in renal fibrosis
Interactions of transforming growth factor-β and angiotensin II in renal fibrosis
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DOI：
10.1161/01.hyp.31.1.181
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发表时间：
1998-01-01
期刊：
影响因子：
8.3
通讯作者：
Noble, NA
中科院分区：
文献类型：
--
作者：
Border, WA;Noble, NA
转化生长因子-β的过度产生清楚地成为许多实验和人类疾病中组织纤维化的基础。转化生长因子-β的强大的纤维化作用来自于同时刺激基质蛋白合成、抑制基质降解和促进基质组装的增强的整联蛋白表达。在动物中，通过静脉注射、瞬时基因转移或转基因插入过度表达转化生长因子-β已表明肾脏对快速纤维化高度敏感。在人类疾病中似乎也是如此，在肾小球肾炎、糖尿病肾病和高血压肾小球损伤中已证明存在过量的转化生长因子β。肾脏对纤维化的特殊易感性的一个可能解释可能是最近发现的肾素-血管紧张素系统和转化生长因子-β之间的生物学复杂相互作用。肾小球血流动力学的改变可以激活肾素-血管紧张素系统和转化生长因子-β。肾素-血管紧张素系统的组分起作用以进一步刺激转化生长因子-β和纤溶酶原激活物抑制剂的产生，导致快速基质积累。在血容量不足时，转化生长因子β从肾小球细胞释放，并可能与血管紧张素II协同作用，加重血管收缩和急性肾衰竭。肾素-血管紧张素系统和转化生长因子-β的相互作用具有重要的临床意义。在实验性和人类肾脏疾病中抑制肾素-血管紧张素系统的保护作用与抑制转化生长因子-β的产生密切相关。这表明，除了血压，转化生长因子β应该是一个治疗目标。可能需要更高剂量或不同的阻断肾素-血管紧张素系统的药物组合或全新的药物策略来实现更大的抗纤维化作用。
Overproduction of transforming growth factor-beta clearly underlies tissue fibrosis in numerous experimental and human diseases. Transforming growth factor-beta's powerful fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation, and enhanced integrin expression that facilitates matrix assembly. In animals, overexpression of transforming growth factor-beta by intravenous injection, transient gene transfer, or transgene insertion has shown that the kidney is highly susceptible to rapid fibrosis. The same seems true in human disease, where excessive transforming growth factor-beta has been demonstrated in glomerulonephritis, diabetic nephropathy, and hypertensive glomerular injury. A possible explanation for the kidney's particular susceptibility to fibrosis may be the recent discovery of biologically complex interactions between the renin-angiotensin system and transforming growth factor-beta. Alterations in glomerular hemodynamics can activate both the renin-angiotensin system and transforming growth factor-beta. Components of the renin-angotensin system act to further stimulate production of transforming growth factor-beta and plasminogen activator inhibitor leading to rapid matrix accumulation. In volume depletion, transforming growth factor-beta is released from juxtaglomerular cells and may act synergistically with angiotensin II to accentuate vasoconstriction and acute renal failure. Interaction of the renin-angiotensin system and transforming growth factor-beta has important clinical implications. The protective effect of inhibition of the renin-angiotensin system in experimental and human kidney diseases correlates closely with the suppression of transforming growth factor-beta production. This suggests that transforming growth factor-beta, in addition to blood pressure, should be a therapeutic target. Higher doses or different combinations of drugs that block the renin-angiotensin system or entirely new drug strategies may be needed to achieve a greater antifibrotic effect.