Molecular mechanisms attributed to colistin renal proximal tubular epithelial cytotoxicity.

Abstract

Colistin is an antibiotic that belongs to the polymyxin family. It has reemerged as a treatment of last resort against multi-drug resistant gram-negative bacterial infections. Nephrotoxicity remains the most daunting and limiting adverse effect of colistin therapy leading to treatment discontinuation and mortality in high-risk patients. Nephrotoxicity occurs secondary to the accumulation of colistin in the renal proximal tubular epithelial cells (RPTECs). Mechanistically, colistin exerts endoplasmic reticulum and ribotoxic stress, induces mitochondrial dysfunction and oxidative stress in the RPTECs leading to apoptosis and necrosis. Moreover, colistin activates the mitogen-activated protein kinases and perturbs the balance between survival-promoting and death-promoting growth factors. In this review we have presented and integrated the major in vitro and in vivo mechanistic studies undertaken to study colistin-induced nephrotoxicity. In addition, we have suggested a possible unifying mechanism for colistin renal toxicity based on the emerging concept of the cross-organelle stress response.