Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome.
Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome.
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DOI：
10.1016/j.ebiom.2020.103162
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发表时间：
2021-01
期刊：
影响因子：
11.1
通讯作者：
Fornoni A
中科院分区：
文献类型：
--
作者：
Kim JJ;David JM;Wilbon SS;Santos JV;Patel DM;Ahmad A;Mitrofanova A;Liu X;Mallela SK;Ducasa GM;Ge M;Sloan AJ;Al-Ali H;Boulina M;Mendez AJ;Contreras GN;Prunotto M;Sohail A;Fridman R;Miner JH;Merscher S;Fornoni A
盘状结构域受体1（DDR 1）是一种受体酪氨酸激酶，其被参与纤维化疾病的发病机制的胶原激活。有趣的是，已经在Col 4a 3敲除小鼠（Alport综合征的小鼠模型（AS小鼠））中观察到I型胶原（Col I）的从头产生。在AS小鼠中缺失DDR 1显示出改善存活率和肾功能。然而，驱动DDR 1依赖性纤维化的机制在很大程度上仍然未知。采用Real-time PCR和Western blot分析足细胞pDDR 1水平、胶原和分化簇36（CD 36）表达。使用Bodipy染色和酶分析测定脂滴积累和含量。通过免疫共沉淀法测定CD 36和DDR 1的相互作用。对从依折麦布和/或雷米普利或溶剂处理的AS小鼠中收获的肾脏进行肌酐、BUN、白蛋白尿、脂质含量以及组织学和形态学评估。我们证明了Col I介导的DDR 1激活诱导了CD 36介导的足细胞脂毒性损伤。我们发现依折麦布在体外干扰CD 36/DDR 1相互作用，并防止AS小鼠的脂毒性，从而与雷米普利相似地保护肾功能。我们的研究表明，Col I/DDR 1介导的脂毒性有助于AS的肾功能衰竭，靶向这一途径可能代表AS和与Col 4突变相关的慢性肾脏疾病（CKD）患者的新治疗策略。本研究得到NIH赠款R 01 DK 117599、R 01 DK 104753、R 01 CA 227493、U 54 DK 083912、UM 1DK 100846、U 01 DK 116101、UL 1 TR 000460的支持（迈阿密临床转化科学研究所，国家推进转化科学中心和国家少数民族健康和健康差异研究所），F32 DK 115109，Hoffmann-La Roche和Alport综合征基金会。
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is activated by collagens that is involved in the pathogenesis of fibrotic disorders. Interestingly, de novo production of the collagen type I (Col I) has been observed in Col4a3 knockout mice, a mouse model of Alport Syndrome (AS mice). Deletion of the DDR1 in AS mice was shown to improve survival and renal function. However, the mechanisms driving DDR1-dependent fibrosis remain largely unknown. Podocyte pDDR1 levels, Collagen and cluster of differentiation 36 (CD36) expression was analyzed by Real-time PCR and Western blot. Lipid droplet accumulation and content was determined using Bodipy staining and enzymatic analysis. CD36 and DDR1 interaction was determined by co-immunoprecipitation. Creatinine, BUN, albuminuria, lipid content, and histological and morphological assessment of kidneys harvested from AS mice treated with Ezetimibe and/or Ramipril or vehicle was performed. We demonstrate that Col I-mediated DDR1 activation induces CD36-mediated podocyte lipotoxic injury. We show that Ezetimibe interferes with the CD36/DDR1 interaction in vitro and prevents lipotoxicity in AS mice thus preserving renal function similarly to ramipril. Our study suggests that Col I/DDR1-mediated lipotoxicity contributes to renal failure in AS and that targeting this pathway may represent a new therapeutic strategy for patients with AS and with chronic kidney diseases (CKD) associated with Col4 mutations. This study is supported by the NIH grants R01DK117599, R01DK104753, R01CA227493, U54DK083912, UM1DK100846, U01DK116101, UL1TR000460 (Miami Clinical Translational Science Institute, National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities), F32DK115109, Hoffmann-La Roche and Alport Syndrome Foundation.
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DOI：
10.1083/jcb.201505067
发表时间：
2015-10-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Choudhary V;Ojha N;Golden A;Prinz WA
通讯作者：
Prinz WA
影响因子：
56.9
作者：
BARKER, DF;HOSTIKKA, SL;TRYGGVASON, K
通讯作者：
TRYGGVASON, K
影响因子：
56.9
作者：
Altmann, SW;Davis, HR;Graziano, MP
通讯作者：
Graziano, MP
影响因子：
30.8
作者：
Boute, N;Gribouval, O;Antignac, C
通讯作者：
Antignac, C
影响因子：
13.6
作者：
Byron, Adam;Randles, Michael J.;Lennon, Rachel
通讯作者：
Lennon, Rachel