Enteropeptidase inhibition improves kidney function in a rat model of diabetic kidney disease.
anti-diabetic drug
diabetic nephropathy
drug development
Journal
Diabetes, obesity & metabolism
ISSN: 1463-1326
Titre abrégé: Diabetes Obes Metab
Pays: England
ID NLM: 100883645
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
10
06
2020
revised:
10
08
2020
accepted:
31
08
2020
pubmed:
8
9
2020
medline:
6
7
2021
entrez:
7
9
2020
Statut:
ppublish
Résumé
To examine the effects of an enteropeptidase inhibitor, SCO-792, on kidney function in rats. The pharmacological effects of SCO-792 were evaluated in Wistar fatty (WF) rats, a rat model of diabetic kidney disease (DKD). Oral administration of SCO-792 increased faecal protein content and improved glycaemic control in WF rats. SCO-792 elicited a rapid decrease in urine albumin-to-creatinine ratio (UACR). SCO-792 also normalized glomerular hyperfiltration and decreased fibrosis, inflammation and tubular injury markers in the kidneys. However, pioglitazone-induced glycaemic improvement had no effect on kidney variables. Dietary supplementation of amino acids (AAs), which bypass the action of enteropeptidase inhibition, mitigated the effect of SCO-792 on UACR reduction, suggesting a pivotal role for enteropeptidase. Furthermore, autophagy activity in the glomerulus, which is impaired in DKD, was elevated in SCO-792-treated rats. Finally, a therapeutically additive effect on UACR reduction was observed with a combination of SCO-792 with irbesartan, an angiotensin II receptor blocker. This study is the first to demonstrate that enteropeptidase inhibition is effective in improving disease conditions in DKD. SCO-792-induced therapeutic efficacy is likely to be independent of glycaemic control and mediated by the regulation of AAs and autophagy. Taken together with a combination effect of irbesartan, SCO-792 may be a novel therapeutic option for patients with DKD.
Identifiants
pubmed: 32893449
doi: 10.1111/dom.14190
pmc: PMC7756647
doi:
Substances chimiques
Enteropeptidase
EC 3.4.21.9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
86-96Informations de copyright
© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
Références
PLoS One. 2016 Dec 16;11(12):e0168396
pubmed: 27992511
Lancet. 2019 Jan 5;393(10166):31-39
pubmed: 30424892
Kidney Int. 1992 Oct;42(4):1006-11
pubmed: 1453577
Cell Mol Biol Lett. 2016 Dec 13;21:29
pubmed: 28536631
Am J Physiol Renal Physiol. 2015 Jul 1;309(1):F2-23
pubmed: 25925260
J Vis Exp. 2018 Nov 1;(141):
pubmed: 30451231
Curr Opin Clin Nutr Metab Care. 2017 Jan;20(1):77-85
pubmed: 27801685
Diabetes. 2015 May;64(5):1555-63
pubmed: 25475435
Am J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1009-22
pubmed: 21228342
Am J Physiol. 1994 Nov;267(5 Pt 2):F703-8
pubmed: 7977774
Clin J Am Soc Nephrol. 2017 Aug 7;12(8):1366-1373
pubmed: 28280116
J Cell Sci. 2004 Jun 1;117(Pt 13):2805-12
pubmed: 15169837
Diabetes. 1981 Dec;30(12):1045-50
pubmed: 7030830
Front Biosci (Elite Ed). 2009 Jun 01;1:242-9
pubmed: 19482641
Diabetes. 2017 Feb;66(2):235-240
pubmed: 28108603
Kidney Int. 2016 Nov;90(5):950-964
pubmed: 27325184
Diabetes Obes Metab. 2021 Jan;23(1):86-96
pubmed: 32893449
Pharmacol Res Perspect. 2019 Sep 04;7(5):e00517
pubmed: 31508234
Proc Soc Exp Biol Med. 1994 Jun;206(2):114-8
pubmed: 8208733
Kidney Int Rep. 2017 Aug 30;3(1):105-114
pubmed: 29340320
J Am Soc Nephrol. 2013 Feb;24(2):198-207
pubmed: 23291473
N Engl J Med. 2019 Jun 13;380(24):2295-2306
pubmed: 30990260
J Clin Invest. 2010 Apr;120(4):1084-96
pubmed: 20200449
Eur J Pharmacol. 2016 Nov 15;791:8-24
pubmed: 27568833
Hypertens Res. 2003 Apr;26(4):339-47
pubmed: 12733703
Nat Rev Nephrol. 2018 Jul;14(7):442-456
pubmed: 29760448
Diabetes Obes Metab. 2019 Oct;21(10):2228-2239
pubmed: 31144422
J Proteome Res. 2014 Jul 3;13(7):3455-66
pubmed: 24933025
Am J Physiol Renal Physiol. 2008 Apr;294(4):F697-701
pubmed: 18272603
Diabetes Metab Syndr. 2017 Nov;11 Suppl 1:S133-S139
pubmed: 27993541
Nephrol Dial Transplant. 2015 Jan;30(1):6-8
pubmed: 25358494
Kidney Int. 1992 Nov;42(5):1207-16
pubmed: 1453605
Amino Acids. 2015 Oct;47(10):2065-88
pubmed: 24965527
Cardiovasc Drugs Ther. 2017 Dec;31(5-6):579-592
pubmed: 28956186
Am J Nephrol. 2011;34(3):268-80
pubmed: 21822010
Nat Commun. 2020 Jun 19;11(1):3148
pubmed: 32561715
Nutrients. 2018 Apr 27;10(5):
pubmed: 29702558
Trends Biochem Sci. 1989 Mar;14(3):110-2
pubmed: 2658218
Curr Opin Pharmacol. 2017 Apr;33:34-40
pubmed: 28482281