The role of the tricellular junction protein ILDR2 in glomerulopathies: Expression patterns and functional insights
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
Affiliations
Florian Siegerist
Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
Felix Kliewe
Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
Elke Hammer
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Paul Schakau
Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
Joanne Ern Chi Soh
Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
Claudia Weber
Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
Maja Lindenmeyer
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Simone Reichelt-Wurm
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
Vedran Drenic
NIPOKA GmbH, Center of High-End Imaging, Greifswald, Germany
Christos Chatziantoniou
National Institute for Health and Medical Research (INSERM), Unité Mixte de Recherche (UMR)-S1155, Tenon Hospital, Sorbonne Universités, Paris, France
Christos E. Chadjichristos
National Institute for Health and Medical Research (INSERM), Unité Mixte de Recherche (UMR)-S1155, Tenon Hospital, Sorbonne Universités, Paris, France
Yiying Zhang
Vagelos College of Physicians and Surgeons, Medical School of Columbia University, New York, NY, USA
Stefan Simm
Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany; Institute of Bioanalysis, Coburg University of Applied Sciences, Coburg, Germany
Miriam C. Banas
Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
Matthias Nauck
Institute for Clinical Chemistry and Laboratory Medicine, University Medicine, Greifswald, Germany
Uwe Völker
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Nicole Endlich
Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany; NIPOKA GmbH, Center of High-End Imaging, Greifswald, Germany; Corresponding author
Summary: 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.
