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bioRxiv · 10.1101/2024.12.21.629915

The IQGAP1-Claudin Cell Junction Axis in Cisplatin-induced Kidney Damage

Barudi, Y.·Fan, X.·Jenkins, K. W.·Dey, S. K.·Yakirevich, E.·Osman, M. A.
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Abstract

Kidney damage resulting from nephrotoxicity is a major side effect of chemotherapy. Cisplatin is an effective antineoplastic agent broadly used in oncology where it interferes with DNA replication in dividing cells, however, its mechanism in kidney damage remains unclear. We tested the hypothesis that cisplatin displaces cell-contact proteins such as IQGAP1-claudin complex in the kidney tubules, causing epithelial cell dissociation and kidney damage. Employing a multifaceted approach, using mutant analyses and optimal cisplatin dose, this hypothesis was tested in cell culture and iqgap1-/- mouse models. Cisplatin inhibited cell proliferation and migration in an IQGAP1-dependent manner, displaced IQGAP1 from cell junctions and altered the expression level of key junctional markers, including claudins 2/4/8 and nephrin. Similar effects were observed in animal models where cisplatin treatment and loss of IQGAP1 had additive effects. These functional outcomes are accounted for by suppression of Akt1/PKB survival and ERK1/2 proliferation signals and activation of JNK-GSK3{beta} stress and inflammatory signal, widely implicated in kidney injury. These findings present IQGAP1-claudin axis as biomarkers and therapeutic targets in kidney damage and pave the way for formulating new analogs that eliminate cisplatin adverse side effects while preserving its antineoplastic efficacy.

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Barudi, Y., Fan, X., Jenkins, K. W., Dey, S. K., Yakirevich, E., Osman, M. A.. 2024-12-22. The IQGAP1-Claudin Cell Junction Axis in Cisplatin-induced Kidney Damage. https://doi.org/10.1101/2024.12.21.629915

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