Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime.
Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime.
复制标题
DOI：
10.1186/s12967-018-1524-5
复制
发表时间：
2018-06-01
影响因子：
7.4
通讯作者：
Prunotto M
中科院分区：
文献类型：
--
作者：
Moll S;Yasui Y;Abed A;Murata T;Shimada H;Maeda A;Fukushima N;Kanamori M;Uhles S;Badi L;Cagarelli T;Formentini I;Drawnel F;Georges G;Bergauer T;Gasser R;Bonfil RD;Fridman R;Richter H;Funk J;Moeller MJ;Chatziantoniou C;Prunotto M
盘状蛋白结构域受体 1 (DDR1) 是一种胶原蛋白激活受体酪氨酸激酶，广泛涉及癌症、动脉粥样硬化和纤维化等疾病。使用基因删除或基因沉默方法进行的多项临床前研究表明，该受体是纤维化和肾小球硬化症的主要驱动目标。本研究调查了 DDR1 在人类新月体肾小球肾炎 (GN) 中的作用和相关性。首先使用免疫组织化学方法，使用新型选择性抗 DDR1 抗体在人类 GN 活检中详细表征了详细的 DDR1 表达。随后，在肾毒性血清 (NTS) GN 模型中采用预防方案，并在 NEP25 GN 小鼠模型中采用治疗干预方案，使用高度选择性的新型小分子抑制剂研究了 DDR1 的保护作用。 DDR1 表达主要限于肾上皮。在人类中，DDR1 在受损的足细胞、表达壁上皮细胞 (PEC) 和足细胞标记物的桥接细胞以及在人类 GN 中形成细胞新月体的 PEC 子集中被高度诱导。 NTS 中 DDR1 的药理学抑制可改善肾功能和组织学参数。使用预防方案获得的这些结果在使用治疗干预方案的 NEP25 GN 小鼠模型中得到了证实。 NTS 的基因表达分析表明，DDR1 的药理学阻断可特异性恢复纤维化和炎症基因网络，并调节肾小球细胞基因特征的表达，进一步验证 DDR1 作为足细胞和 PEC 中细胞命运的主要介质。总之，这些结果表明，DDR1 抑制可能是治疗肾小球肾炎的一种有吸引力且有前途的药物干预措施，主要是通过靶向肾上皮。本文的在线版本 (10.1186/s12967-018-1524-5) 包含补充材料，可供授权用户使用。
Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase extensively implicated in diseases such as cancer, atherosclerosis and fibrosis. Multiple preclinical studies, performed using either a gene deletion or a gene silencing approaches, have shown this receptor being a major driver target of fibrosis and glomerulosclerosis. The present study investigated the role and relevance of DDR1 in human crescentic glomerulonephritis (GN). Detailed DDR1 expression was first characterized in detail in human GN biopsies using a novel selective anti-DDR1 antibody using immunohistochemistry. Subsequently the protective role of DDR1 was investigated using a highly selective, novel, small molecule inhibitor in a nephrotoxic serum (NTS) GN model in a prophylactic regime and in the NEP25 GN mouse model using a therapeutic intervention regime. DDR1 expression was shown to be mainly limited to renal epithelium. In humans, DDR1 is highly induced in injured podocytes, in bridging cells expressing both parietal epithelial cell (PEC) and podocyte markers and in a subset of PECs forming the cellular crescents in human GN. Pharmacological inhibition of DDR1 in NTS improved both renal function and histological parameters. These results, obtained using a prophylactic regime, were confirmed in the NEP25 GN mouse model using a therapeutic intervention regime. Gene expression analysis of NTS showed that pharmacological blockade of DDR1 specifically reverted fibrotic and inflammatory gene networks and modulated expression of the glomerular cell gene signature, further validating DDR1 as a major mediator of cell fate in podocytes and PECs. Together, these results suggest that DDR1 inhibition might be an attractive and promising pharmacological intervention for the treatment of GN, predominantly by targeting the renal epithelium. The online version of this article (10.1186/s12967-018-1524-5) contains supplementary material, which is available to authorized users.
登录
查看更多内容
DOI：
10.1016/b978-0-12-800180-6.00002-5
发表时间：
2014
影响因子：
--
作者：
Leitinger, Birgit
通讯作者：
Leitinger, Birgit
影响因子：
6.1
作者：
Iyoda, Masayuki;Shibata, Takanori;Akizawa, Tadao
通讯作者：
Akizawa, Tadao
影响因子：
7.3
作者：
MORLEY, AR;WHEELER, J
通讯作者：
WHEELER, J
影响因子：
9.2
作者：
Valiathan, Rajeshwari R.;Marco, Marta;Leitinger, Birgit;Kleer, Celina G.;Fridman, Rafael
通讯作者：
Fridman, Rafael
影响因子：
3.7
作者：
Kabgani N;Grigoleit T;Schulte K;Sechi A;Sauer-Lehnen S;Tag C;Boor P;Kuppe C;Warsow G;Schordan S;Mostertz J;Chilukoti RK;Homuth G;Endlich N;Tacke F;Weiskirchen R;Fuellen G;Endlich K;Floege J;Smeets B;Moeller MJ
通讯作者：
Moeller MJ