Influence of Dipeptidyl Peptidase-IV Inhibitor Sitagliptin on Extracellular Signal-Regulated Kinases 1/2 Signaling in Rats with Diabetic Nephropathy

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Abstract

The protective effects of sitagliptin on the kidneys of rats with diabetic nephropathy (DN) and its influence on extracellular signal-regulated kinases 1/2 (ERK1/2) signaling were investigated. Male Wistar rats ( n = 40) were randomly assigned to normal control, DN, low-dose sitagliptin intervention (ST1), or high-dose sitagliptin intervention (ST2) groups. Animals were euthanized after a 16-week treatment, and blood glucose (BG), glycosylated hemoglobin (HbA1c), urinary albumin excretion rate (AER), serum creatinine (Scr), creatinine clearance rate (Ccr), active glucagon-like peptide-1 (GLP-1) levels, kidney hypertrophy index, and renal pathohistology were determined. Immunohistochemical methods and real-time polymerase chain reaction (PCR) were used to detect protein and mRNA expression of podocalyxin, ERK1/2, GLP-1 receptor (GLP-1R) and transforming growth factor-β (TGF-β). After 16 weeks, BG, AER, Scr, HbA1c and the kidney hypertrophy index were all significantly decreased ( p < 0.05) in ST1 and ST2 groups, while Ccr and active GLP-1 levels were increased ( p < 0.05), with changes more pronounced in ST2 ( p < 0.05). Glomerular pathological lesions were also improved following sitagliptin treatment, especially in ST2. Immunohistochemical and real-time PCR revealed that protein and mRNA expression levels of podocalyxin and GLP-1R were increased significantly in ST1 and ST2, while expression of ERK1/2 and TGF-β was decreased ( p < 0.05). Sitagliptin therefore delayed DN progression, possibly via the inhibition of ERK1/2 signaling and promotion of the interaction between GLP-1 and the GLP-1R.

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Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

Erin Mulvihill, Daniel Drucker (2014)

Abstract Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.

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Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen.

Munehiro Kitada, Yasuhito Ishigaki, Daisuke Koya … (2014)

Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2-induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment. © 2014 by the American Diabetes Association.

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GIP and GLP‐1, the two incretin hormones: Similarities and differences

Yutaka Seino, Mitsuo Fukushima, Daisuke Yabe (2010)

Abstract Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP‐1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which belong to the G‐protein coupled receptor family. Receptor binding activates and increases the level of intracellular cyclic adenosine monophosphate in pancreatic β cells, thereby stimulating insulin secretion glucose‐dependently. In addition to their insulinotropic effects, GIP and GLP‐1 play critical roles in various biological processes in different tissues and organs that express GIPR and GLP‐1R, including the pancreas, fat, bone and the brain. Within the pancreas, GIP and GLP‐1 together promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass, while GIP enhances postprandial glucagon response and GLP‐1 suppresses it. In adipose tissues, GIP but not GLP‐1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP‐1 inhibits bone absorption. In the brain, both GIP and GLP‐1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP‐1 and their insulinotropic effects on β cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects. We summarize here the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic β cells, and their non‐insulinotropic effects, and discuss their potential in treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00022.x, 2010)

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Author and article information

Journal

Journal ID (publisher-id): PHA

Journal ID (nlm-ta): Pharmacology

Journal ID (doi): 10.1159/issn.0031-7012

Title: Pharmacology

Abbreviated Title: Pharmacology

Publisher: S. Karger AG (Basel, Switzerland karger@ 123456karger.com http://www.karger.com )

ISSN (Print): 0031-7012

ISSN (Electronic): 1423-0313

Publication date (Print): May 2017

Publication date (Electronic): 23 March 2017

Volume: 100

Issue: 1-2

Pages: 1-13

Affiliations

^aDepartment of Nephrology, Shanxi Dayi Hospital (Shanxi Academy of Medical Sciences), ^bPostdoctoral Workstation of the Second Hospital of Shanxi Medical University, ^cDepartment of Nephrology, The People Hospital of Shanxi Province, ^dDepartment of Microbiology and Immunology, Shanxi Medical University, and ^eDepartment of Nephrology, Shanxi Provincial Corps Hospital of Chinese People Armed Police Forces, Taiyuan, China

Author notes

*Prof. Weimin Yu, Department of Nephrology, Shanxi Dayi Hospital (Shanxi Academy of Medical Sciences), 99 Longcheng Street Taiyuan, Shanxi 030032 (China), E-Mail ywm4158963@163.com

Article

Publisher ID: 455874 Other ID: Pharmacology 2017;100:1-13

DOI: 10.1159/000455874

PubMed ID: 28329747

SO-VID: 39b834fa-7c4e-4176-af16-76e9dfa64373

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 12 August 2016

Date accepted : 05 January 2017

Page count

Figures: 7, Tables: 5, References: 53, Pages: 13

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Influence of Dipeptidyl Peptidase-IV Inhibitor Sitagliptin on Extracellular Signal-Regulated Kinases 1/2 Signaling in Rats with Diabetic Nephropathy

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Karger: Nutrition and Dietetics

Most cited references 43

Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen.

GIP and GLP‐1, the two incretin hormones: Similarities and differences

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