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ResearchIn-Press PreviewCell biologyImmunologyNephrology Open Access | 10.1172/jci.insight.198363

Functional characterization of podocyte-expressed THSD7A in experimental membranous nephropathy

Ming Huang,1 Moritz Lassé,1 Silke Dehde,1 Felicitas E. Hengel,1 Fatih Demir,2 Anja M. Billing,2 Ning Song,1 Larissa Seifert,1 Oliver Kretz,1 Florian Grahammer,1 Ulf Panzer,1 Sebastian Brähler,3 Tobias B. Huber,1 Gunther Zahner,4 Markus M. Rinschen,2 and Nicola M. Tomas4

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Huang, M. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Lassé, M. in: PubMed | Google Scholar |

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Dehde, S. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Hengel, F. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Demir, F. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Billing, A. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Song, N. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Seifert, L. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Kretz, O. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Grahammer, F. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Panzer, U. in: PubMed | Google Scholar |

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Brähler, S. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Huber, T. in: PubMed | Google Scholar |

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Zahner, G. in: PubMed | Google Scholar

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Rinschen, M. in: PubMed | Google Scholar |

1III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2Department of Biomedicine, Aarhus University, Aarhus, Denmark

3Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Cologne, Germany

4III. Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany

Find articles by Tomas, N. in: PubMed | Google Scholar |

Published February 26, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.198363.
Copyright © 2026, Huang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 26, 2026 - Version history
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Abstract

While the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a knockout (Thsd7a–/–) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. While Thsd7a–/– mice only displayed a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactomic analysis identified a protein complex including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.

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  • Version 1 (February 26, 2026): In-Press Preview
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