Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway

Esther Civantos,1,2 Enrique Bosch,1 Elisa Ramirez,1 Olha Zhenyukh,1 Jesús Egido,1,2 Oscar Lorenzo,1,2 Sebastián Mas1,2 1Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Autonoma University, 2CIBERDEM (Biomedical Rese...

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Autores principales:	Civantos E, Bosch E, Ramirez E, Zhenyukh O, Egido J, Lorenzo O, Mas S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	diabetes sitagliptin Nrf2 Keap-1 miRNAs GK rats Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/37695bd2614b4590baaf7e315f2384d4
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spelling	oai:doaj.org-article:37695bd2614b4590baaf7e315f2384d42021-12-02T03:58:44ZSitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway1178-7007https://doaj.org/article/37695bd2614b4590baaf7e315f2384d42017-06-01T00:00:00Zhttps://www.dovepress.com/sitagliptin-ameliorates-oxidative-stress-in-experimental-diabetic-neph-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Esther Civantos,1,2 Enrique Bosch,1 Elisa Ramirez,1 Olha Zhenyukh,1 Jesús Egido,1,2 Oscar Lorenzo,1,2 Sebastián Mas1,2 1Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Autonoma University, 2CIBERDEM (Biomedical Research Centre in Diabetes and Associated Metabolic Disorders), Madrid, Spain Background: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor used in type 2 diabetes therapy, has demonstrated protective effects in diabetic chronic kidney disease, in part due to its pleiotropic actions. However, its potential direct effects on the kidney are still not completely defined. Here, by means of proteomics and miRNA profiling, we have further unveiled the role of sitagliptin in oxidative stress, as well as the underlying mechanisms.Methods: Renal cortex samples from 9-month-old wild-type (Wistar), type II diabetic Goto-Kakizaki (GK) and sitagliptin-treated GK rats (GK+Sita) (10 mg kg−1 per day) were subjected to quantitative miRNA transcriptomic array, immunohistochemistry and Western blot studies. Renal GK and GK+Sita samples were also analyzed by differential in-gel electrophoresis. Bioinformatic tools were used to find out the relationships between altered proteins and related miRNA expression. Studies were also carried out in cultured tubular cells to confirm in vivo data.Results: Diabetic GK rats exhibited proteinuria, renal interstitial inflammatory infiltrates and fibrosis, which improved by 20 weeks of sitagliptin treatment. Proteomic analysis of diabetic GK and Wistar rats showed a differential expression of 39 proteins mostly related to oxidative stress and catabolism. In addition, 15 miRNAs were also significantly altered in GK rats.Conclusion: Treatment with sitagliptin was associated with modulation of antioxidant response in the diabetic kidney, involving a downregulation of miR-200a, a novel Keap-1 inhibitor and miR-21, coincidentally with the clinical and the morphological improvement. These data further support the concept that DPP-4 inhibitors could exert a direct reno-protective effect in patients with diabetic nephropathy. Keywords: diabetes, sitagliptin, Nrf2, Keap-1, miRNAs, GK ratsCivantos EBosch ERamirez EZhenyukh OEgido JLorenzo OMas SDove Medical PressarticlediabetessitagliptinNrf2Keap-1miRNAsGK ratsSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 10, Pp 207-222 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	diabetes sitagliptin Nrf2 Keap-1 miRNAs GK rats Specialties of internal medicine RC581-951
spellingShingle	diabetes sitagliptin Nrf2 Keap-1 miRNAs GK rats Specialties of internal medicine RC581-951 Civantos E Bosch E Ramirez E Zhenyukh O Egido J Lorenzo O Mas S Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway
description	Esther Civantos,1,2 Enrique Bosch,1 Elisa Ramirez,1 Olha Zhenyukh,1 Jesús Egido,1,2 Oscar Lorenzo,1,2 Sebastián Mas1,2 1Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Autonoma University, 2CIBERDEM (Biomedical Research Centre in Diabetes and Associated Metabolic Disorders), Madrid, Spain Background: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor used in type 2 diabetes therapy, has demonstrated protective effects in diabetic chronic kidney disease, in part due to its pleiotropic actions. However, its potential direct effects on the kidney are still not completely defined. Here, by means of proteomics and miRNA profiling, we have further unveiled the role of sitagliptin in oxidative stress, as well as the underlying mechanisms.Methods: Renal cortex samples from 9-month-old wild-type (Wistar), type II diabetic Goto-Kakizaki (GK) and sitagliptin-treated GK rats (GK+Sita) (10 mg kg−1 per day) were subjected to quantitative miRNA transcriptomic array, immunohistochemistry and Western blot studies. Renal GK and GK+Sita samples were also analyzed by differential in-gel electrophoresis. Bioinformatic tools were used to find out the relationships between altered proteins and related miRNA expression. Studies were also carried out in cultured tubular cells to confirm in vivo data.Results: Diabetic GK rats exhibited proteinuria, renal interstitial inflammatory infiltrates and fibrosis, which improved by 20 weeks of sitagliptin treatment. Proteomic analysis of diabetic GK and Wistar rats showed a differential expression of 39 proteins mostly related to oxidative stress and catabolism. In addition, 15 miRNAs were also significantly altered in GK rats.Conclusion: Treatment with sitagliptin was associated with modulation of antioxidant response in the diabetic kidney, involving a downregulation of miR-200a, a novel Keap-1 inhibitor and miR-21, coincidentally with the clinical and the morphological improvement. These data further support the concept that DPP-4 inhibitors could exert a direct reno-protective effect in patients with diabetic nephropathy. Keywords: diabetes, sitagliptin, Nrf2, Keap-1, miRNAs, GK rats
format	article
author	Civantos E Bosch E Ramirez E Zhenyukh O Egido J Lorenzo O Mas S
author_facet	Civantos E Bosch E Ramirez E Zhenyukh O Egido J Lorenzo O Mas S
author_sort	Civantos E
title	Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway
title_short	Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway
title_full	Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway
title_fullStr	Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway
title_full_unstemmed	Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway
title_sort	sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the mir-200a/keap-1/nrf2 antioxidant pathway
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/37695bd2614b4590baaf7e315f2384d4
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Sitagliptin ameliorates oxidative stress in experimental diabetic nephropathy by diminishing the miR-200a/Keap-1/Nrf2 antioxidant pathway

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