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

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.

Protection of Hesperidin against Methotrexate- Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

“…The cross-talk between these pathways has indeed been previously reported, where upregulation of renal Nrf2/ HO-1 was concomitantly encountered together with a decrease in renal TNF-α by ergothioneine in cisplatininduced nephrotoxicity, 34 by phenethyl isothiocyanate in streptozotocin-induced diabetic nephropathy, 35 and by quercetin on copper sulfate-induced nephrotoxicity. 36 Similar findings have been reported linking the upregulation of renal Nrf2/HO-1 to caspase 3 downregulation by ergothioneine in cisplatin-induced nephrotoxicity, 34 by camel milk in cyclosporine-induced nephrotoxicity, 37 and by thymoquinone in diclofenacinduced acute kidney injury. 38 However, despite all previous reports, it is extremely difficult to hypothesize a cause-effect relationship between these complex pathways.…”

Extracellular cyclophilins A and C induce dysfunction of pancreatic microendothelial cells

“…In this case, LPS did not affect eNOS activation, however, treatment with 0.2 μM CsA alone decreased the enzyme activation (Figures 4A,B). This effect of CsA on eNOS activity has been previously reported and is related to the effects of the drug on intracellular pathways (Arab et al, 2021;Harb et al, 2021). eCypA also reduced eNOS phosphorylation, showing levels of 33.0 ± 10.4% (p < 0.01).…”

Protective effect of quercetin on kidney diseases: From chemistry to herbal medicines

“…The production of free radicals and ROS are key triggers for the activation of Nrf2 (nuclear factor erythroid 2-related factor 2) and HO-1 (renal heme oxygenase 1). Regarding nephrotoxicity, Nrf2/HO-1 pathway may play an important role in boosting the GSH, GPx, and SOD antioxidant moieties (Arab et al, 2021). Quercetin supplementation could markedly activate the mRNA expression of Nrf2 and HO-1 in copper sulfateinduced renal injury mice (Peng et al, 2020).…”