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Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury

BACKGROUND AND PURPOSE: 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....

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Autores principales: Mostafa, Rasha Ezzat, Morsi, Azza Hassan, Asaad, Gihan Farag
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer - Medknow 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407158/
https://www.ncbi.nlm.nih.gov/pubmed/34522201
http://dx.doi.org/10.4103/1735-5362.323920
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author Mostafa, Rasha Ezzat
Morsi, Azza Hassan
Asaad, Gihan Farag
author_facet Mostafa, Rasha Ezzat
Morsi, Azza Hassan
Asaad, Gihan Farag
author_sort Mostafa, Rasha Ezzat
collection PubMed
description BACKGROUND AND PURPOSE: 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: 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: 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 via alleviation of all the above-mentioned parameters when compared to DXR-control rats. CONCLUSION AND IMPLICATIONS: 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.
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spelling pubmed-84071582021-09-13 Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury Mostafa, Rasha Ezzat Morsi, Azza Hassan Asaad, Gihan Farag Res Pharm Sci Original Article BACKGROUND AND PURPOSE: 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: 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: 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 via alleviation of all the above-mentioned parameters when compared to DXR-control rats. CONCLUSION AND IMPLICATIONS: 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. Wolters Kluwer - Medknow 2021-08-19 /pmc/articles/PMC8407158/ /pubmed/34522201 http://dx.doi.org/10.4103/1735-5362.323920 Text en Copyright: © 2021 Research in Pharmaceutical Sciences https://creativecommons.org/licenses/by-nc-sa/4.0/This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
spellingShingle Original Article
Mostafa, Rasha Ezzat
Morsi, Azza Hassan
Asaad, Gihan Farag
Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury
title Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury
title_full Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury
title_fullStr Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury
title_full_unstemmed Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury
title_short Anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of NLRP3 inflammasome up-regulation and tubulo-interstitial injury
title_sort anti-inflammatory effects of saxagliptin and vildagliptin against doxorubicin-induced nephrotoxicity in rats: attenuation of nlrp3 inflammasome up-regulation and tubulo-interstitial injury
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407158/
https://www.ncbi.nlm.nih.gov/pubmed/34522201
http://dx.doi.org/10.4103/1735-5362.323920
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