Inhibiting the urokinase-type plasminogen activator receptor system recovers STZ-induced diabetic nephropathy.
Animals
Diabetes Mellitus, Experimental
/ chemically induced
Diabetic Nephropathies
/ chemically induced
Inflammation
/ metabolism
Kidney
/ metabolism
Male
Podocytes
/ metabolism
Rats
Rats, Sprague-Dawley
Receptors, Urokinase Plasminogen Activator
/ metabolism
Signal Transduction
/ physiology
Streptozocin
/ pharmacology
Up-Regulation
/ physiology
Urokinase-Type Plasminogen Activator
/ metabolism
AQP2 expression and localization
ECM markers and renal fibrosis
UPARANT (Cenupatide)
diabetic kidney disease
glomerular morphology and filtration barrier
inflammation markers
standard renal parameters
uPAR pathway
vascular permeability
αvβ3 integrin/Rac-1 pathway
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
20
07
2018
revised:
03
10
2018
accepted:
12
10
2018
pubmed:
15
11
2018
medline:
18
6
2020
entrez:
15
11
2018
Statut:
ppublish
Résumé
The urokinase-type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR -(s)uPAR- from circulation) is to regulate podocyte function through αvβ3 integrin/Rac-1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)-induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, αvβ3 integrin/Rac-1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ-induced up-regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the αvβ3 integrin/Rac-1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen-plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR-targeting approaches.
Identifiants
pubmed: 30426662
doi: 10.1111/jcmm.14004
pmc: PMC6349167
doi:
Substances chimiques
Receptors, Urokinase Plasminogen Activator
0
Streptozocin
5W494URQ81
Urokinase-Type Plasminogen Activator
EC 3.4.21.73
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1034-1049Informations de copyright
© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Références
J Chromatogr B Analyt Technol Biomed Life Sci. 2016 May 1;1020:142-7
pubmed: 27038650
Mol Cancer Ther. 2014 May;13(5):1092-104
pubmed: 24705350
Evid Based Complement Alternat Med. 2018 Feb 14;2018:5180165
pubmed: 29636780
Nat Med. 2008 Jan;14(1):55-63
pubmed: 18084301
Eur J Pharmacol. 2016 Nov 15;791:8-24
pubmed: 27568833
J Diabetes Complications. 2016 Nov - Dec;30(8):1440-1442
pubmed: 27475262
Clin Exp Pharmacol Physiol. 2017 Apr;44(4):509-521
pubmed: 28079268
Mol Cell Endocrinol. 2012 Oct 15;362(1-2):183-93
pubmed: 22732364
J Am Soc Nephrol. 2006 Feb;17(2):368-77
pubmed: 16394109
Pflugers Arch. 2017 Aug;469(7-8):1017-1020
pubmed: 28689240
Invest Ophthalmol Vis Sci. 2017 Jun 1;58(7):3138-3148
pubmed: 28632880
Prog Mol Biol Transl Sci. 2017;148:31-65
pubmed: 28662825
J Histochem Cytochem. 2012 Dec;60(12):976-86
pubmed: 23103723
Pflugers Arch. 2017 Nov;469(11):1415-1423
pubmed: 28656379
Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F914-F925
pubmed: 28228402
Curr Opin Nephrol Hypertens. 2013 Sep;22(5):551-8
pubmed: 23852332
J Diabetes Res. 2017;2017:2904150
pubmed: 29464181
J Cell Biol. 2015 Apr 27;209(2):199-210
pubmed: 25918223
Invest Ophthalmol Vis Sci. 2016 Oct 1;57(13):5723-5735
pubmed: 27787560
Diabetologia. 2017 Apr;60(4):719-728
pubmed: 28083635
Eur J Pharmacol. 2017 Oct 5;812:196-205
pubmed: 28633927
Biomed Pharmacother. 2017 Sep;93:276-285
pubmed: 28648975
Nephrol Dial Transplant. 2012 May;27(5):1746-55
pubmed: 22076430
Kidney Res Clin Pract. 2018 Jun;37(2):106-111
pubmed: 29971205
Nephrology (Carlton). 2007 Jun;12(3):261-6
pubmed: 17498121
J Cell Mol Med. 2019 Feb;23(2):1034-1049
pubmed: 30426662
BMC Endocr Disord. 2017 Aug 3;17(1):48
pubmed: 28774305
Korean J Intern Med. 2017 Jan;32(1):11-25
pubmed: 28049280
J Diabetes Investig. 2015 Jan;6(1):3-15
pubmed: 25621126
IUBMB Life. 2005 Jun;57(6):441-7
pubmed: 16012053
Am J Physiol Renal Physiol. 2003 Aug;285(2):F303-9
pubmed: 12697581
Mol Med Rep. 2017 May;15(5):3172-3178
pubmed: 28339051
J Cardiovasc Pharmacol. 2014 Feb;63(2):158-66
pubmed: 24220312
Diabetol Metab Syndr. 2014 Feb 12;6(1):17
pubmed: 24520999
Inflamm Res. 2017 Aug;66(8):701-709
pubmed: 28456844
Am J Physiol Renal Physiol. 2016 Mar 15;310(6):F547-59
pubmed: 26719366
J Diabetes. 2017 Apr;9(4):332-340
pubmed: 27121697
J Lab Clin Med. 2004 Aug;144(2):69-77
pubmed: 15322501
Biomed Pharmacother. 2017 Jul;91:425-435
pubmed: 28475921
Science. 2018 Apr 20;360(6386):254-258
pubmed: 29674575
Biochimie. 2014 Nov;106:101-10
pubmed: 25151412
Biomed Pharmacother. 2018 May;101:510-527
pubmed: 29505922
PLoS One. 2013 Nov 07;8(11):e80328
pubmed: 24244677
Eur J Pharmacol. 2017 Jul 15;807:12-20
pubmed: 28438648
J Diabetes Res. 2017;2017:3232848
pubmed: 28596971
Med Sci Monit Basic Res. 2016 Dec 16;22:165-174
pubmed: 27980322
Br J Pharmacol. 2013 Sep;170(2):426-39
pubmed: 23826864
J Am Soc Nephrol. 2006 Nov;17(11):2999-3012
pubmed: 17035608
Int J Mol Sci. 2017 Apr 30;18(5):
pubmed: 28468297
Endocrinology. 2007 Mar;148(3):1118-30
pubmed: 17138647
Mol Cancer Ther. 2013 Oct;12(10):1981-93
pubmed: 23939376
Invest Ophthalmol Vis Sci. 2016 May 1;57(6):2600–2611
pubmed: 27168367
Pharmacol Res. 2015 Dec;102:184-91
pubmed: 26466865
Int J Nanomedicine. 2017 Oct 24;12:7799-7813
pubmed: 29123394
BMC Cancer. 2014 Aug 30;14:639
pubmed: 25175595
Cold Spring Harb Perspect Biol. 2009 Dec;1(6):a001651
pubmed: 20457564
Curr Vasc Pharmacol. 2017;15(6):557-565
pubmed: 28155628
Expert Rev Mol Med. 2009 Apr 28;11:e13
pubmed: 19397838
Acta Physiol (Oxf). 2015 Nov;215(3):144-58
pubmed: 26332853
Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2392-407
pubmed: 25766585
Nat Med. 2011 Jul 31;17(8):952-60
pubmed: 21804539