FP229
EPITHELIAL-MESENCHYMAL TRANSITION MAY BE BLOCKED BEFORE ACUTE KIDNEY INJURY EXPANSION

INTRODUCTION AND AIMS: Cisplatin is a major chemotherapeutic drug for the treatment of solid tumors, but its nephrotoxicity is a major complication and a dose limiting factor for anticancer therapy. Some evidences have shown that epithelial-mesenchymal transititon (EMT) contributes to the progression from acute renal failure to chronic renal failure. We have found that cilastatin, a renal dehydrodipeptidase I inhibitor has protective effects on kidneys from cisplatin-induced damage. In this study we investigated whether the protective effects of cilastatin are related to the prevention of the EMT-induced by cisplatin.

METHODS: Male Wistar rats were divided into 4 groups: control rats, cilastatin-control rats, cisplatin-injected rats, cilastatin-treated cisplatin-injected rats. Nephrotoxicity was assessed 5 days after cisplatin treatment, by measuring serum creatinine, blood urea nitrogen (BUN), glomerular filtration ratio, proteinuria and renal morphology. Some typical markers of EMT and cell-cell adhesion were measured by western blot and immunohistochemical studies.

RESULTS: Cisplatin-treated rats showed significant elevations in BUN, creatinine, and proteinuria and decreased the glomerular filtration rate when compared with control rats. Cisplatin rats also exhibited severe morphological changes such as vacuolization and hyaline cast in the tubular lumen. Cilastatin significantly prevented partial or totally these changes in renal function and ameliorated histological damage in cisplatin-treated animals. On the other hand, cisplatin increased transforming growth factor beta (TGFβ, an inducer of EMT) and vimentin (mesenchymal cell marker) levels while decreased significantly β-catenin and zonula occludens-1 (ZO-1) levels, both proteins involved in cell adhesion. Cilastatin treatment reversed these changes.

CONCLUSIONS: This study provides evidence that the protection offered by cilastatin to acute renal failure-induced by cisplatin, is associated to the prevention of the EMT by decreasing the signaling pathways that cause it and avoiding the loss of cell junctions. EMT signals seem to be triggered during the acute kidney injury expansion phase.