Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine-induced nephrotoxicity: Targeting Nrf2/HO-1 and AKT/eNOS/NO pathways

Hany H Arab; Ahmed H Eid; Amany M Gad; Rania Yahia; Ayman M Mahmoud; Ahmed M Kabel

doi:10.1002/fsn3.2277

Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine-induced nephrotoxicity: Targeting Nrf2/HO-1 and AKT/eNOS/NO pathways

Food Sci Nutr. 2021 Apr 5;9(6):3177-3190. doi: 10.1002/fsn3.2277. eCollection 2021 Jun.

Authors

Hany H Arab¹, Ahmed H Eid², Amany M Gad^{2

3}, Rania Yahia², Ayman M Mahmoud^{4

5}, Ahmed M Kabel⁶

Affiliations

¹ Department of Pharmacology and Toxicology College of Pharmacy Taif University Taif Saudi Arabia.
² Department of Pharmacology Egyptian Drug Authority (EDA), formerly NODCAR Giza Egypt.
³ Department of Pharmacology and Toxicology Faculty of Pharmacy Sinai University El Ismailia Egypt.
⁴ Zoology Department, Faculty of Science Beni-Suef University Beni-Suef Egypt.
⁵ Biotechnology Department Research Institute of Medicinal and Aromatic Plants Beni-Suef University Beni-Suef Egypt.
⁶ Department of Pharmacology Faculty of Medicine Tanta University Tanta Egypt.

Abstract

Cyclosporine (CsA) is a widely used immunosuppressive agent that incurs marked nephrotoxicity in the clinical setting. Thus, there is a need for finding safe/effective agents that can attenuate CsA-induced kidney injury. Meanwhile, the underlying mechanisms for CsA-associated nephrotoxicity are inadequately investigated, in particular, the AKT/eNOS/NO pathway. Here, the present work aimed to explore the potential of camel milk, a natural product with distinguished antioxidant/anti-inflammatory actions, to ameliorate CsA-induced nephrotoxicity in rats. The molecular mechanisms related to renal oxidative aberrations and apoptosis were studied, including Nrf2/HO-1 and AKT/eNOS/NO pathways. The kidney tissues were inspected using histopathology, ELISA, Western blotting, and immunohistochemistry. The present findings demonstrated that camel milk (10 ml/kg) significantly lowered creatine, BUN, and NGAL nephrotoxicity markers and the aberrant histopathology, with similar efficacy to the reference quercetin. Moreover, camel milk suppressed the renal oxidative stress, as evidenced by significantly lowering NOX-1 and lipid peroxides and significantly augmenting the renal antioxidant moieties (GSH, GPx, and SOD), thereby, driving the restoration of Nrf2/HO-1 pathway. Meanwhile, camel milk counteracted the pro-apoptotic reactions by significantly lowering Bax protein expression, caspase-3 activity/cleavage, and PARP cleavage, alongside significantly increasing the expression of the proliferation signal PCNA. Regarding the anti-apoptotic AKT/eNOS/NO pathway, camel milk activated its signaling by significantly increasing the protein expression of PI3Kp110, p-AKT(Ser473)/total AKT, and p-eNOS (Ser1177)/total eNOS besides significantly boosting the renoprotective NO levels. In conclusion, these findings reveal that camel milk may be a promising candidate for the alleviation of CsA-induced nephrotoxicity.

Keywords: AKT; Nrf2; apoptosis; camel milk; cyclosporine; oxidative stress.