The Regulation of MAGI2 and its Diagnostic Application in Podocytopathies

Siegerist, F.; Hay, E.; Hammer, E.; Iervolino, A.; Weber, C.; Dikou, J. S.; Stamellou, E.; Butt, L.; Benzing, T.; Wiech, T.; Brinkkoetter, P.; Zimmermann, U.; Capasso, G.; Chatziantoniou, C.; Chadjichristos, C.; Huber, T. B.; Voelker, U.; Schindler, M.; Endlich, N.

doi:10.1101/2024.12.01.626009

bioRxiv · 10.1101/2024.12.01.626009

The Regulation of MAGI2 and its Diagnostic Application in Podocytopathies

Siegerist, F.·Hay, E.·Hammer, E.·Iervolino, A.·Weber, C.·Dikou, J. S.·Stamellou, E.·Butt, L.·Benzing, T.·Wiech, T.·Brinkkoetter, P.·Zimmermann, U.·Capasso, G.·Chatziantoniou, C.·Chadjichristos, C.·Huber, T. B.·Voelker, U.·Schindler, M.·Endlich, N.

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Abstract

Podocyte dysfunction is central to various glomerular diseases, necessitating reliable biomarkers for early detection and diagnosis. This study investigates the regulatory mechanisms of membrane-associated guanylate kinase inverted 2 (MAGI2) and its potential as a biomarker for podocytopathies. The expression of the gene coding for the scaffolding protein MAGI2 was examined across four species and demonstrated to be conserved within the podocyte filtration slit. In vitro and in vivo studies using isolated glomeruli and mammalian animal models of glomerular disease, including DOCA-salt hypertension, nephrotoxic serum nephritis, and puromycin aminonucleoside nephropathy, demonstrated significant downregulation of MAGI2 in injured podocytes. This downregulation was also conserved in a zebrafish model of focal and segmental glomerulosclerosis (FSGS), and the podocyte-specific MAGI2 ortholog Magi2a was reduced post podocyte injury. CRISPR/Cas9-generated zebrafish mutants for magi2a exhibited marked glomerular filtration barrier defects and downregulation of nephrin, underscoring MAGI2s critical role in podocyte function. Human biopsy analyses revealed differential MAGI2 expression: it was increased in minimal change disease (MCD) patients but significantly decreased in primary, but not secondary FSGS cases. As MAGI2 localization did not change in disease states it is an alternative marker for super-resolution microscopy-based morphometry of the filtration slit, correlating with nephrin-based measurements. These findings highlight the potential of MAGI2 as a sensitive biomarker for podocyte injury and its diagnostic utility in differentiating between primary FSGS and MCD.

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Siegerist, F., Hay, E., Hammer, E., Iervolino, A., Weber, C., Dikou, J. S., Stamellou, E., Butt, L., Benzing, T., Wiech, T., Brinkkoetter, P., Zimmermann, U., Capasso, G., Chatziantoniou, C., Chadjichristos, C., Huber, T. B., Voelker, U., Schindler, M., Endlich, N.. 2024-12-02. The Regulation of MAGI2 and its Diagnostic Application in Podocytopathies. https://doi.org/10.1101/2024.12.01.626009

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