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Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway.
Life Sci. 2021 Jan 01; 264:118630.LS

Abstract

AIM

Cyclophosphamide (CP) is an effective anticancer and immunosuppressive agent. However, it induces nephrotoxicity that limits its use. This study explored the effect of H2S, an important biological signaling molecule with a cytoprotective activity, on CP-induced nephrotoxicity.

METHODS

Male Wistar rats were treated with saline or NaHS (100 μM/kg/day, H2S donor) or dl-propargylglycine (PAG) (30 mg/kg/day, H2S blocker) for 10 days before a single i.p injection of CP (200 mg/kg). Then, rats were sacrificed, and renal functions were assessed in serum. Histopathological changes, as well as oxidant defenses, inflammatory and apoptotic markers in the renal tissue, were evaluated.

KEY FINDINGS

Pretreatment with NaHS significantly reduced the urea and creatinine levels that were elevated in CP-intoxicated rats. NaHS increased the expression of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2) and its subsequent antioxidant proteins; heme oxygenase-1 (HO-1), NAD(P) H quinone oxidoreductase 1 (NQO1), reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, NaHS prohibited the histopathological damage induced by CP. The inhibition of caspase-3 and nuclear factor kappa B (NF-κB) supported the protective role of H2S against CP-induced kidney damage. On the other hand, blocking endogenous H2S did not provide a more significant deterioration in CP-induced nephrotoxicity in terms of oxidative stress or inflammatory status.

SIGNIFICANCE

Exogenous H2S donors exhibited a protective effect against CP-induced nephrotoxicity, which may be mediated via the Nrf2/HO-1/NF-κB signaling pathway. However, endogenous H2S may be insufficient to protect the cell against the induced oxidative damage. This approach provides a novel target to prevent nephrotoxicity of CP.

Authors+Show Affiliations

Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, Egypt. Electronic address: shaimaaminia@mu.edu.eg.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt.Department of Biochemistry, Faculty of Pharmacy, MTI University, Cairo, Egypt.Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33169683

Citation

Waz, Shaimaa, et al. "Nephroprotective Effect of Exogenous Hydrogen Sulfide Donor Against Cyclophosphamide-induced Toxicity Is Mediated By Nrf2/HO-1/NF-κB Signaling Pathway." Life Sciences, vol. 264, 2021, p. 118630.
Waz S, Heeba GH, Hassanin SO, et al. Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway. Life Sci. 2021;264:118630.
Waz, S., Heeba, G. H., Hassanin, S. O., & Abdel-Latif, R. G. (2021). Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway. Life Sciences, 264, 118630. https://doi.org/10.1016/j.lfs.2020.118630
Waz S, et al. Nephroprotective Effect of Exogenous Hydrogen Sulfide Donor Against Cyclophosphamide-induced Toxicity Is Mediated By Nrf2/HO-1/NF-κB Signaling Pathway. Life Sci. 2021 Jan 1;264:118630. PubMed PMID: 33169683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway. AU - Waz,Shaimaa, AU - Heeba,Gehan Hussein, AU - Hassanin,Soha Osama, AU - Abdel-Latif,Rania G, Y1 - 2020/10/22/ PY - 2020/06/10/received PY - 2020/10/06/revised PY - 2020/10/17/accepted PY - 2020/11/11/pubmed PY - 2021/1/16/medline PY - 2020/11/10/entrez KW - Cyclophosphamide KW - HO-1 KW - Hydrogen sulfide KW - Nephrotoxicity KW - Nrf2 SP - 118630 EP - 118630 JF - Life sciences JO - Life Sci VL - 264 N2 - AIM: Cyclophosphamide (CP) is an effective anticancer and immunosuppressive agent. However, it induces nephrotoxicity that limits its use. This study explored the effect of H2S, an important biological signaling molecule with a cytoprotective activity, on CP-induced nephrotoxicity. METHODS: Male Wistar rats were treated with saline or NaHS (100 μM/kg/day, H2S donor) or dl-propargylglycine (PAG) (30 mg/kg/day, H2S blocker) for 10 days before a single i.p injection of CP (200 mg/kg). Then, rats were sacrificed, and renal functions were assessed in serum. Histopathological changes, as well as oxidant defenses, inflammatory and apoptotic markers in the renal tissue, were evaluated. KEY FINDINGS: Pretreatment with NaHS significantly reduced the urea and creatinine levels that were elevated in CP-intoxicated rats. NaHS increased the expression of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2) and its subsequent antioxidant proteins; heme oxygenase-1 (HO-1), NAD(P) H quinone oxidoreductase 1 (NQO1), reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, NaHS prohibited the histopathological damage induced by CP. The inhibition of caspase-3 and nuclear factor kappa B (NF-κB) supported the protective role of H2S against CP-induced kidney damage. On the other hand, blocking endogenous H2S did not provide a more significant deterioration in CP-induced nephrotoxicity in terms of oxidative stress or inflammatory status. SIGNIFICANCE: Exogenous H2S donors exhibited a protective effect against CP-induced nephrotoxicity, which may be mediated via the Nrf2/HO-1/NF-κB signaling pathway. However, endogenous H2S may be insufficient to protect the cell against the induced oxidative damage. This approach provides a novel target to prevent nephrotoxicity of CP. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/33169683/Nephroprotective_effect_of_exogenous_hydrogen_sulfide_donor_against_cyclophosphamide_induced_toxicity_is_mediated_by_Nrf2/HO_1/NF_κB_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(20)31383-7 DB - PRIME DP - Unbound Medicine ER -