Abstract
Background
Carfilzomib (CFZ), a proteasome inhibitor approved by the FDA to treat multiple myeloma, may cause nephrotoxicity.
Hypothesis
Rutin is a bioflavonoid with antioxidant properties. We aimed to examine whether rutin protects the kidney from CFZ-induced nephrotoxicity.
Study design
This study aimed to demonstrate the effect of rutin on CFZ-induced renal injury via the inhibition of oxidative stress and inflammation.
Methods
Wistar albino rats were divided into six groups (n = 6): Group 1 (normal control; NC) was administered normal saline for 3 weeks; Group 2 (CFZ/toxic group) received CFZ [4 mg/kg, intraperitoneal (i.p.) injection] twice weekly for 3 weeks; Group 3 (standard treatment group) was administered CFZ (4 mg/kg, i.p.) and olmesartan (2 mg/kg, p.o.) for 3 weeks; Group 4 was administered CFZ (4 mg/kg, i.p.) and rutin (10 mg/kg, p.o.) for 3 weeks; Group 5 was administered CFZ (4 mg/kg, i.p.) and rutin (20 mg/kg, p.o.) for 3 weeks; and Group 6 was administered CFZ (4 mg/kg, i.p.) and rutin (40 mg/kg, p.o.) for 3 weeks. We carried out haematological and biochemical analyses, determined oxidative stress, caspase-3 activity, and protein levels, and performed a histopathological evaluation to confirm CFZ-induced nephrotoxicity and its prevention by rutin administration.
Results
Exposure to only CFZ significantly (p < 0.05) increased white blood cell (WBC) count, Hb%, and HTC% concentration; however, these features were significantly decreased (p < 0.05) when olmesartan and rutin were administered. CFZ administration significantly decreased (p < 0.0001) the level of antioxidant enzymes; whereas, administration of olmesartan and rutin significantly reversed (p < 0.05) their levels toward the normal range. The levels of caspase-3 enzyme significantly increased (p < 0.001) in the CFZ group and were reduced toward the normal values by olmesartan and rutin administration. Furthermore, the results of NOS-2, NF-κB, IkBa, and IL-17 protein estimation and the histopathological evaluation strengthened our findings that rutin exhibits a protective effect against CFZ-induced nephrotoxicity.
Conclusion
These findings clearly demonstrate that rutin ameliorates CFZ-induced oxidative stress and inflammation in nephrotoxicity via the NOS-mediated NF-κB signaling pathway.
Abbreviations
- ANOVA:
-
Analysis of variance
- BUN:
-
Blood urea nitrogen
- CAT:
-
Catalase
- CFZ:
-
Carfilzomib
- FDA:
-
Food and Drug Application
- GFR:
-
Glomerular filtration rate
- GR:
-
Glutathione reductase
- GSH:
-
Reduced glutathione
- H&E:
-
Hematoxylin and eosin
- Hb:
-
Hemoglobin
- HTC:
-
Hematocrit
- i.p.:
-
Intraperitoneal
- IkB-α:
-
Inhibitory kappa-B alpha
- IL:
-
Interleukin
- AMDA:
-
Malondialdehyde
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- NC:
-
Normal control
- NF-κB:
-
Nuclear factor kappa-B
- NOS:
-
Nitric oxide synthase
- p.o.:
-
Per oral
- RBC:
-
Red blood cells
- RhoA:
-
Ras homolog gene family, member A
- ROCK:
-
Rho-associated kinase (rho-kinase)
- SEM:
-
Standard error of mean
- TBA:
-
Thiobarbituric acid
- TGF-β:
-
Transforming growth factors
- WBC:
-
White blood cells
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Acknowledgements
The present work was funded by King Saud University, Deanship of Scientific Research, College of Pharmacy (project no. RGP-VPP-305). The authors would like to thank the Department of Pharmacology and Toxicology at the College of Pharmacy, King Saud University for granting us permission to use its facilities.
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Al-Harbi, N.O., Imam, F., Al-Harbi, M.M. et al. Rutin inhibits carfilzomib-induced oxidative stress and inflammation via the NOS-mediated NF-κB signaling pathway. Inflammopharmacol 27, 817–827 (2019). https://doi.org/10.1007/s10787-018-0550-5
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DOI: https://doi.org/10.1007/s10787-018-0550-5