The nephroprotective effect of Quercetin in Cyclophosphamide-induced renal toxicity might be associated with MAPK/ERK and NF-κB signal modulation activity

Abstract

The present study aimed to examine the protective effect of quercetin (QUE) on cyclophosphamide (CTX)-induced nephrotoxicity. For that purpose, 24 mice were divided into four groups (Control, QUE, CTX, and CTX + QUE). The CTX and CTX + QUE groups received 200 mg/kg of cyclophosphamide on the 1^st and 7^th days. The QUE and CTX + QUE groups were treated with 50 mg/kg of quercetin daily for 14 days. At the end of the experiment, the animals were sacrificed, and kidney samples were analyzed. The results indicated that CTX leads to severe morphological degenerations and disruption in renal function. Serum BUN, Creatinine, Uric acid, tissue Bax, Caspase 3, TNF-α and IL-1β expression levels were upregulated in the CTX group compared to Control and QUE groups (p < 0.05). Although MAPK/ERK phosphorylation level is not affected in CTX group, there was a significant increase in CTX + QUE group (p < 0.05), but the NF-κB was significantly suppressed in this group (p < 0.01). The RT-qPCR results showed that the cyt-c and the Bax/Bcl-2 ratio mRNA expression folds were upregulated in the CTX group (p < 0.01), which was downregulated in the CTX + QUE group. However, there was a significant difference in the CTX + QUE group compared to the Control and QUE groups (p < 0.01). The findings showed that administering quercetin along with cyclophosphamide alleviated renal injury by regulating apoptotic and inflammatory expression. Moreover, the administration of quercetin and cyclophosphamide could synergistically improve renal function test results, and activate cellular responses, which upmodulate MAPK/ERK phosphorylation and suppression of NF-κB.

Graphical abstract

Twenty-four mice were equally divided into 4 groups (Control, QUE, CTX, CTX + QUE). CTX (1). CTX + QUE groups received 200 mg/kg Cyclophosphamide at 1^st and 7^th days of study (2). Animals in QUE and CTX + QUE received 50 mg/kg quercetin daily for 14 days (3). All animals were euthanized (4) and kidney samples were used for microscopic, western blotting and RT-qPCR analysis (5). Cyclophosphamide exposure increased expression of inflammatory (6) TNF-α, IL-1β, and (7) pro-apoptotic Bax, Caspase 3, cyt-c, and gold standard Bax/Bcl-2 ratio. Quercetin treatment alleviated inflammatory cytokine (8) and apoptotic protein expression levels (9). This process might be modulated through increased MAPK/ERK phosphorylation level which potentially regulate the suppression process of NF-κB level (10).

Keywords:

• Cyclophosphamide
• quercetin
• nephrotoxicity
• apoptosis
• MAPK/ERK
• NF-κB

Acknowledgement

The authors would like to thank to Associate Professor Serdal Kurt and Associate Professor Funda Eski for their valuable contributions. We are also gratitude to the Assistant Professor Gul Sahika Gokdemir for her valuable contributions in renal function test analysis.

Authors’ contribution

U.S.: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing - Original Draft, Visualization, Writing - Review & Editing D.E.K: Formal analysis, Investigation, Writing - Original Draft, F.Z.D.: Validation, Investigation, S.K.: Formal analysis, Investigation, S.I.K.: Formal analysis, Investigation, Writing - Original Draft, Writing - Review & Editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data of this study will be available from corresponding authors upon an acceptable reason.

Additional information

Funding

The author(s) reported there is no funding associated with the work ­featured in this article.