Acute renal failure resulting from anti-cancer drug (e.g. cisplatin) administration in cancer treatment is the most common adverse effect limiting therapeutic efficacy. Cisplatin-induced nephrotoxicity is primarily associated with pathological alterations of proximal tubule epithelial cells (PTECs), including reorganisation of the actin cytoskeleton, disruption of cell-cell and cell-matrix adhesions, and apoptosis. Epac (Exchange Protein activated by cAMP) is an activator of the small GTPase Rap, which functions as a pivotal regulator of cell adhesion. Of all organs, Epac is most highly expressed in the kidney, being particularly enriched in tubule epithelium, suggesting a functional role here for Epac-Rap signalling. In this study, we will use both experimental in vitro and in vivo models for cisplatin exposure, to investigate the effect of activation of the Epac-Rap pathway on adhesion of proximal tubule epithelia and the consequent protection against cisplatin-induced nephrotoxicity.

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