Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

• Published in: Cellular physiology and biochemistry Vol. 46; no. 4; pp. 1628 - 1642
• Main Authors: Arab, Hany H., Salama, Samir A., Maghrabi, Ibrahim A.
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01-01-2018; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: 5-fluorouracil; Akt; Animals; Antioxidants; Antioxidants - metabolism; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Blood Urea Nitrogen; Camel milk; Camelus - metabolism; Cancer; Cell Line, Tumor; Creatinine - analysis; Cytokines; Cytokines - metabolism; Diabetes; Down-Regulation - drug effects; Fluorouracil - toxicity; HCT116 Cells; Heme Oxygenase-1 - metabolism; Hep G2 Cells; Humans; Kidney - drug effects; Kidney - injuries; Kinases; Laboratory animals; Lipocalin-2 - analysis; MAPKs; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; MCF-7 Cells; Metabolism; Milk - chemistry; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; NADPH Oxidase 1 - metabolism; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-κB; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Original Paper; Oxidative stress; Oxidative Stress - drug effects; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Wistar; Rodents; Signal Transduction - drug effects; Tumor Suppressor Protein p53 - metabolism; Saudi Arabia; United States > US; 5-fluorouracil; Camel milk; NF-κB; Akt; PI3K; MAPKs
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000489210

Background/Aims: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. Methods: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting. Results: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use. Conclusion: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.