Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury.
Doxorubicin
Inflammation
Nephrotoxicity
Saxagliptin
Tubulo-interstitial injury
Vildagliptin
Journal
Research in pharmaceutical sciences
ISSN: 1735-5362
Titre abrégé: Res Pharm Sci
Pays: Iran
ID NLM: 101516968
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
received:
18
10
2020
revised:
25
12
2020
accepted:
23
05
2021
entrez:
15
9
2021
pubmed:
16
9
2021
medline:
16
9
2021
Statut:
epublish
Résumé
The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats. Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/kg) and VIL (10 mg/kg) for 2 weeks. DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1β, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
The clinical use of the chemotherapeutic drug, doxorubicin (DXR), is significantly limited by its extensive multi-organ toxicity. Dipeptidyl peptidase-4 (DPP4) is over-expressed in oxidative stress, inflammation and apoptosis. DPP4 inhibitors have proven pleiotropic effects. The study investigates the protective effects of some DDP4 inhibitors; namely, saxagliptin (SAX) and vildagliptin (VIL) against DXR-induced nephrotoxicity in rats.
EXPERIMENTAL APPROACH
METHODS
Forty rats were divided into 4 groups. Group I served as normal control. Nephrotoxicity was induced in the remaining 3 groups by single-DXR injection (15 mg/kg, i.p.). Groups III and IV administered oral SAX (10 mg/kg) and VIL (10 mg/kg) for 2 weeks.
FINDINGS/RESULTS
RESULTS
DXR-control rats showed deteriorated renal functions, elevated renal inflammatory parameters (tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and inducible nitric oxide synthase (iNOS)), up-regulated nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome and significant tubulointerstitial injury manifested by elevated neutrophil gelatinase-associated lipocalin concentration and distorted renal histopathological pictures. Immunohistochemical studies showed increased iNOS and Bax positivity in renal tissues of DXR-control rats. Treatment with SAX and VIL significantly attenuated DXR-induced nephrotoxicity
CONCLUSION AND IMPLICATIONS
CONCLUSIONS
The study elucidated the possible mechanisms beyond DXR-induced nephrotoxicity to be through inflammation plus tubulointerstitial injury. DXR nephrotoxicity has been linked to TNF-α, IL-1β, and NLRP3 inflammasome up-regulation and iNOS expression. The protective role of SAX and VIL in mitigating the tubular injury and inflammatory effects of DXR on renal tissues has been tested and proved.
Identifiants
pubmed: 34522201
doi: 10.4103/1735-5362.323920
pii: RPS-16-547
pmc: PMC8407158
doi:
Types de publication
Journal Article
Langues
eng
Pagination
547-558Informations de copyright
Copyright: © 2021 Research in Pharmaceutical Sciences.
Déclaration de conflit d'intérêts
The authors declared no conflict of interest in this study.
Références
Clin Pharmacokinet. 2017 Jan;56(1):11-24
pubmed: 27282159
Biomed Pharmacother. 2018 Dec;108:1524-1534
pubmed: 30372854
Arch Toxicol. 2021 Jan;95(1):1-9
pubmed: 32852568
Pharmacol Res. 2009 Nov;60(5):373-81
pubmed: 19467331
Toxicology. 2007 Feb 28;231(1):81-90
pubmed: 17234320
Pharmacology. 2018;101(3-4):219-224
pubmed: 29393264
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Sep;1865(9):158755
pubmed: 32534015
Nephrol Dial Transplant. 2015 May;30(5):706-12
pubmed: 25087196
Clin Exp Med. 2012 Dec;12(4):233-40
pubmed: 22080234
Res Pharm Sci. 2019 Feb;14(1):64-73
pubmed: 30936934
Hum Exp Toxicol. 2021 Feb;40(2):274-283
pubmed: 32812453
J Am Soc Nephrol. 2007 Feb;18(2):407-13
pubmed: 17229907
Science. 2008 May 2;320(5876):674-7
pubmed: 18403674
Nephrology (Carlton). 2016 May;21(5):423-31
pubmed: 26375854
Exp Biol Med (Maywood). 2016 Aug;241(14):1577-87
pubmed: 27037281
Exp Biol Med (Maywood). 2014 Apr;239(4):465-76
pubmed: 24586096
Am J Physiol Renal Physiol. 2015 Apr 15;308(8):F878-87
pubmed: 25656369
Cancer Biol Ther. 2011 Jun 15;11(12):1008-16
pubmed: 21464611
Drug Metab Dispos. 2009 Mar;37(3):536-44
pubmed: 19074975
J Ethnopharmacol. 2013 May 20;147(2):311-20
pubmed: 23518420
Nature. 2009 Mar 26;458(7237):509-13
pubmed: 19158676
Naunyn Schmiedebergs Arch Pharmacol. 2020 Aug;393(8):1383-1390
pubmed: 32036411
Arch Med Res. 2020 Jan;51(1):32-40
pubmed: 32086107
Front Pharmacol. 2019 May 28;10:567
pubmed: 31191310
Inflammation. 2019 Jun;42(3):1056-1070
pubmed: 30737662
PLoS One. 2015 Jun 18;10(6):e0127090
pubmed: 26086199
Scand J Clin Lab Invest Suppl. 2008;241:89-94
pubmed: 18569973
Contrib Nephrol. 2008;160:65-75
pubmed: 18401162
Cell Microbiol. 2008 Jul;10(7):1468-77
pubmed: 18331592
J Toxicol. 2016;2016:9507563
pubmed: 26904117
Environ Toxicol. 2020 Feb;35(2):124-135
pubmed: 31566303
Cancer Biol Ther. 2010 Aug 1;10(3):258-66
pubmed: 20559024
Pathophysiology. 2015 Jun;22(2):117-23
pubmed: 26002558
Life Sci. 2018 Sep 1;208:64-71
pubmed: 30012474
J Toxicol. 2015;2015:424813
pubmed: 26880912
Kidney Int. 2014 Oct;86(4):701-11
pubmed: 25007170
Kidney Blood Press Res. 2018;43(3):987-999
pubmed: 29913457
Curr Opin Nephrol Hypertens. 2015 Jan;24(1):67-73
pubmed: 25415611