Protective effect of mycophenolate mofetil against nephrotoxicity and hepatotoxicity induced by tacrolimus in Wistar rats

Abstract

Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co-administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF's possible protective effect. Our results showed that MMF (at 50 mg kg(-1) body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg(-1) b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process.

Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

“…HK2 and RPTEC/TERT1 cells were treated with CyA and FK506 (10 μM each) for 6 and 24 h, respectively. The dose of 10 μM (CyA 12 μg/mL, FK506 8 μg/mL) is comparable to other studies [17,[39][40][41][42][43] and was identified in dose-response experiments, where HK2 cells were treated with various concentrations of CyA and FK506 (0.1-1000 μM), and 10 μM reflects the lowest dose that yielded a statistically significant decrease in proliferation by at least 20% (Supporting Information Fig. 1).…”

“…The same CyA concentrations (4-40 μg/mL) yielded a G1 and G2/M-phase arrest in LLC-PK1 renal tubule cells [41]. Kim et al [17] used 30 μg/g CyA to induce CIN in mice after 1-4 weeks of treatment, and up to 400 μg/g FK506 was used to induce nephrotoxicity in rats [39]. All these studies, except that of Kim et al, used time periods of 24-72 h, which is similar to our experimental setting.…”

Arsenic and Selenium Profile in Erythrocytes of Renal Transplant Recipients

“…This damage was associated with an increase of DNA fragmentation [2]. Other results suggest that coadministration MMF with tacrolimus protects the liver and kidney against tacrolimus toxicity via an antioxidant process [5]. We have not confirmed the mechanism of action, since that was not the goal of the current study; however, we revealed that the regimen that include MMF increased As and lowered Se level in renal transplant recipients, which seems to be unfavorable in aspect of function of transplanted organ.…”

“…This is an immunomodulatory drug that inhibits inosine monophosphate dehydrogenase (IMPDH). The drug inhibits the proliferation of T and B cells [2][3][4][5]. MMF is mostly codrug with calcineurin inhibitors to prolong allograft function; it is believed that MMF exhibits antioxidant properties [5].…”

Serum Selenium, Iron, Zinc, and Copper Concentrations in Renal Transplant Recipients Treated with Mycophenolate Mofetil

“…Copper is an important trace element that serves as a structural ion in superoxide dismutase (SOD), an antioxidant enzyme that reduces oxidative stress [1]. Our results suggest that MMF evidently increased the level of Cu in blood, which may be associated with the fact that MMF inhibits ROS production by increasing the activity of Cu/Zn SOD [11]. Our findings correlate with those of the study of Kaminska et al [16], who found Cu levels to be significantly higher in blood serum of renal recipients who used MMF than in patients not using MMF [16].…”