Dysfunction of epithelial cell contacts associates with a myriad of human diseases. Cisplatin is an effective antineoplastic agent where it interferes with DNA replication in proliferating cells, but it causes kidney epithelial damage by unclear mechanism(s). We hypothesized that cisplatin displaces the cell-contact proteins IQGAP1-claudin complex in the kidney tubules, potentially causing epithelial cell dissociation implicated in kidney damage. Employing a multifaceted approach, using mutant analyses and a low cisplatin dose, this hypothesis was tested in cell culture and iqgap1−/− murine model. Cisplatin inhibited cell proliferation and migration in an IQGAP1-dependent manner, displaced IQGAP1 from cell junctions and differentially altered the expression level of key junctional markers, including claudins 2/4/8. Similar effects were observed in animal models where cisplatin treatment and loss of IQGAP1 displayed additive effects, particularly in the distal tubules, suggesting secretion and transport defects as underlying factors. These alterations are accompanied by suppression of Akt1/PKB survival and ERK1/2 proliferation signals and activation of JNK-GSK3αβ stress and inflammatory signal. These findings present IQGAP1-claudin axis as a biomarker 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.
Barudi et al. (Tue,) studied this question.