Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease.
Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease.
复制标题
遗传和药理学工具研究盘状蛋白受体在肾脏疾病中的作用。
DOI：
10.3389/fphar.2022.1001122
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
在损伤后，肾脏经历一个修复过程，这导致在几乎没有损伤证据的情况下替换损伤的组织。然而，反复损伤或肾脏无法停止修复过程会导致细胞外基质(ECM)成分的异常沉积，从而导致纤维化和器官功能障碍。ECM成分的合成/降解受到几个因素的精细调控，包括盘状结构域受体(DDRs)。这些是由胶原蛋白激活的受体酪氨酸激酶。一旦激活，DDRs控制着几种细胞功能，当这些功能恶化时，会导致肾脏损伤和纤维化。DDRs在健康的肾脏中检测不到，但在一些肾脏纤维化的情况下会迅速上调，从而使它们成为有吸引力的抗纤维化靶点。DDRs通过促进受损肾脏细胞的凋亡，刺激促炎细胞因子的产生，调节细胞外基质成分的产生，从而促进肾脏损伤和纤维化。它们通过激活规范的细胞内分子或直接与核染色质相互作用并促进促纤维化基因的转录来实现这些效果。本综述的目的是强调DDRs促进肾脏损伤/纤维化的典型和非典型机制。这篇综述将总结利用缺乏DDR的细胞和小鼠获得的主要发现，并将讨论靶向DDR小分子和反义抑制剂的发现和发展。了解DDR控制肾脏损伤和纤维化的分子机制可能不仅使我们能够开发更具选择性和更有效的抑制剂，而且还可以确定何时需要实现DDR抑制来预防和/或阻止肾脏纤维化的发展。
Following injury the kidney undergoes a repair process, which results in replacement of the injured tissue with little evidence of damage. However, repetitive injuries or inability of the kidney to stop the repair process result in abnormal deposition of extracellular matrix (ECM) components leading to fibrosis and organ dysfunction. The synthesis/degradation of ECM components is finely regulated by several factors, including discoidin domain receptors (DDRs). These are receptor tyrosine kinases that are activated by collagens. Upon activation, DDRs control several cell functions that, when exacerbated, contribute to kidney injury and fibrosis. DDRs are undetectable in healthy kidney, but become rapidly upregulated in several kidney fibrotic conditions, thus making them attractive anti-fibrotic targets. DDRs contribute to kidney injury and fibrosis by promoting apoptosis of injured kidney cells, stimulating the production of pro-inflammatory cytokines, and regulating the production of ECM components. They achieve these effects by activating canonical intracellular molecules or by directly interacting with nuclear chromatin and promoting the transcription of pro-fibrotic genes. The goal of this review is to highlight canonical and non-canonical mechanisms whereby DDRs contribute to kidney injury/fibrosis. This review will summarize key findings obtained using cells and mice lacking DDRs and it will discuss the discovery and development of targeted DDR small molecule- and antisense-based inhibitors. Understanding the molecular mechanisms whereby DDRs control kidney injury and fibrosis might enable us to not only develop more selective and potent inhibitors, but to also determine when DDR inhibition needs to be achieved to prevent and/or halt the development of kidney fibrosis.
登录
查看更多内容
DOI：
10.1016/j.bbapap.2012.10.014
发表时间：
2013-10
影响因子：
3.2
作者：
Carafoli, Federico;Hohenester, Erhard
通讯作者：
Hohenester, Erhard
影响因子：
8
作者：
Borza CM;Bolas G;Bock F;Zhang X;Akabogu FC;Zhang MZ;de Caestecker M;Yang M;Yang H;Lee E;Gewin L;Fogo AB;McDonald WH;Zent R;Pozzi A
通讯作者：
Pozzi A
影响因子：
--
作者：
El Azreq MA;Kadiri M;Boisvert M;Pagé N;Tessier PA;Aoudjit F
通讯作者：
Aoudjit F
影响因子：
5.6
作者：
Elkamhawy A;Lu Q;Nada H;Woo J;Quan G;Lee K
通讯作者：
Lee K
DOI：
10.1164/rccm.200603-333oc
发表时间：
2006-08-15
影响因子：
24.7
作者：
Avivi-Green, Carmel;Singal, Mayank;Vogel, Wolfgang F.
通讯作者：
Vogel, Wolfgang F.