Mechanisms of GLP-1 receptor-independent renoprotective effects of the dipeptidyl peptidase type 4 inhibitor linagliptin in GLP-1 receptor knockout mice with 5/6 nephrectomy.
Animals
Collagen Type I
/ metabolism
Collagen Type I, alpha 1 Chain
Dipeptidyl Peptidase 4
/ metabolism
Dipeptidyl-Peptidase IV Inhibitors
/ pharmacology
Disease Models, Animal
Down-Regulation
/ drug effects
Glucagon-Like Peptide-1 Receptor
/ genetics
Heterogeneous Nuclear Ribonucleoprotein A1
/ metabolism
Humans
Kidney
/ drug effects
Linagliptin
/ pharmacology
Male
Mice
Mice, Knockout
Nephrectomy
/ adverse effects
RNA-Seq
Renal Insufficiency, Chronic
/ drug therapy
Signal Transduction
/ drug effects
Thymosin
/ metabolism
Transcription Factors
/ metabolism
Transforming Growth Factor beta1
/ metabolism
Up-Regulation
/ drug effects
Glp1r(−/−) mice
HNRNPA1
TGF-β1
YB-1
chronic kidney disease
collagen I
fibrosis
linagliptin
proteomic analysis
thymosin β4
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
26
04
2018
revised:
14
01
2019
accepted:
17
01
2019
pubmed:
14
4
2019
medline:
22
9
2020
entrez:
14
4
2019
Statut:
ppublish
Résumé
Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham+wild type+placebo; 5/6Nx+ wild type+placebo; 5/6Nx+wild type+linagliptin; sham+knock out+placebo; 5/6Nx+knock out+ placebo; 5/6Nx+knock out+linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin β4 and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-β1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and Glp1r-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1, YB-1, thymosin β4 and TGF-β1) influenced by DPP-4 inhibition.
Identifiants
pubmed: 30979564
pii: S0085-2538(19)30052-3
doi: 10.1016/j.kint.2019.01.010
pii:
doi:
Substances chimiques
Collagen Type I
0
Collagen Type I, alpha 1 Chain
0
Dipeptidyl-Peptidase IV Inhibitors
0
Glp1r protein, mouse
0
Glucagon-Like Peptide-1 Receptor
0
Heterogeneous Nuclear Ribonucleoprotein A1
0
Hnrnpa1 protein, mouse
0
Tgfb1 protein, mouse
0
Transcription Factors
0
Transforming Growth Factor beta1
0
YB-1 protein, mouse
0
Linagliptin
3X29ZEJ4R2
thymosin beta(4)
549LM7U24W
Thymosin
61512-21-8
Dipeptidyl Peptidase 4
EC 3.4.14.5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1373-1388Informations de copyright
Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.