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

Authors Civantos E, Bosch E, Ramirez E, Zhenyukh O, Egido J, Lorenzo O, Mas S

Received 17 January 2017

Accepted for publication 22 March 2017

Published 7 June 2017 Volume 2017:10 Pages 207—222

DOI https://doi.org/10.2147/DMSO.S132537

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Professor Ming-Hui Zou


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

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