The role of the tricellular junction protein ILDR2 in glomerulopathies: Expression patterns and functional insights

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2024-11-07 DOI:10.1016/j.isci.2024.111329

Florian Siegerist , Felix Kliewe , Elke Hammer , Paul Schakau , Joanne Ern Chi Soh , Claudia Weber , Maja Lindenmeyer , Simone Reichelt-Wurm , Vedran Drenic , Christos Chatziantoniou , Christos E. Chadjichristos , Yiying Zhang , Stefan Simm , Miriam C. Banas , Matthias Nauck , Uwe Völker , Nicole Endlich

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Abstract

The tricellular tight junctions are crucial for the regulation of paracellular flux at tricellular junctions, where tricellulin (MARVELD2) and angulins (ILDR1, ILDR2, or LSR) are localized. The role of ILDR2 in podocytes, specialized epithelial cells in the kidney, is still unknown. We investigated the role of ILDR2 in glomeruli and its influence on blood filtration. Western blots, single-cell RNA sequencing (scRNA-seq), and superresolution microscopy showed a strong expression of ILDR2 in podocytes that colocalized with the podocyte-specific claudin CLDN5. Co-immunoprecipitation revealed that ILDR2 interacts with CLDN5. In glomerulopathies, induced by nephrotoxic serum and by desoxycorticosterone acetate (DOCA)-salt heminephrectomy, ILDR2 was strongly up-regulated. Furthermore, Ildr2 knockout mice exhibited glomerular hypertrophy and decreased podocyte density. However, they did not develop effacement of podocyte foot processes or proteinuria. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic analysis of isolated glomeruli showed an increase in matrix proteins, such as fibronectin and collagens. This suggests a protective role of ILDR2 in glomerulopathies.

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三细胞连接蛋白 ILDR2 在肾小球疾病中的作用：表达模式与功能见解

三细胞紧密连接对调节三细胞连接处的旁细胞通量至关重要，三细胞蛋白（MARVELD2）和血管蛋白（ILDR1、ILDR2 或 LSR）定位于三细胞连接处。ILDR2 在荚膜细胞（肾脏中的特化上皮细胞）中的作用尚不清楚。我们研究了 ILDR2 在肾小球中的作用及其对血液过滤的影响。Western印迹、单细胞RNA测序（scRNA-seq）和超分辨率显微镜显示，ILDR2在荚膜细胞中强表达，并与荚膜细胞特异性claudin CLDN5共定位。共免疫沉淀显示，ILDR2 与 CLDN5 相互作用。在肾毒性血清和醋酸去氧皮质酮（DOCA）-盐性半肾切除术诱发的肾小球疾病中，ILDR2强烈上调。此外，Ildr2 基因敲除小鼠表现出肾小球肥大和荚膜细胞密度降低。然而，它们并没有出现荚膜脚突起脱落或蛋白尿。对离体肾小球进行的液相色谱-串联质谱（LC-MS/MS）蛋白质组分析表明，基质蛋白（如纤维连接蛋白和胶原蛋白）有所增加。这表明 ILDR2 在肾小球疾病中起着保护作用。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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