Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings

Cyclosporine A (CsA) is a widely used immunosuppressive agent that greatly reduces the rates of kidney-, heart-, and liver-transplant rejection. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. While the mechanisms underlying CsA nephrotoxicity are still not fully understood, increasing lines of evidence suggest that oxidative stress plays an important role in this phenomenon. Specifically, CsA induces endoplasmic reticulum stress and increases mitochondrial reactive oxygen species production: this modifies the redox balance, which causes lipid peroxidation and thereby induces nephrotoxicity. Recent studies on the pathogenesis of CsA nephrotoxicity suggest that CsA-induced autophagy can alleviate the deleterious effects of CsA-induced endoplasmic reticulum stress, thereby preventing nephrotoxicant-induced renal injury. A variety of signaling pathways participate in the pathogenesis of CsA nephrotoxicity. Specifically, the p38, ERK, and JNK MAPK subfamilies are all involved in CsA nephrotoxicity, while NF-κB is a target molecule of CsA. Moreover, the fibrogenic cytokine TGF-β1 contributes to CsA-induced renal fibrosis, while Nrf2 modulates CsA-induced cellular oxidative stress. In addition, CsA generally inhibits nitric oxide synthesis and impairs endothelium-dependent relaxation in the renal artery. However, some reports also suggest that nitric oxide synthesis is enhanced in the kidney cortex during CsA nephrotoxicity. Notably, the biomarkers of CsA nephrotoxicity associated with CsA have not been reviewed previously. Therefore, in this review, we will first provide an update on CsA nephrotoxicity in humans and describe the potential biomarkers of CsA nephrotoxicity. The molecular and cellular mechanisms that underlie CsA nephrotoxicity and the roles played by oxidative stress, autophagy, and signaling pathways will then be comprehensively summarized and discussed. Finally, the current therapeutical strategies for CsA nephrotoxcixity are summarized. We hope this review will provide a better understanding of CsA nephrotoxicity, thereby improving the management of patients who are treated with CsA.