Cerebral ischemia induces TRPC6 via HIF1α/ZEB2 axis in the glomerular podocytes and contributes to proteinuria.
Actin Cytoskeleton
Animals
Calcium
/ metabolism
Calcium Channel Blockers
/ pharmacology
Cell Line
Disease Models, Animal
Focal Adhesion Protein-Tyrosine Kinases
/ metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Infarction, Middle Cerebral Artery
/ complications
Kidney Glomerulus
/ cytology
Male
Permeability
/ drug effects
Phosphorylation
Podocytes
/ cytology
Proteinuria
/ etiology
Rats
Rats, Sprague-Dawley
TRPC Cation Channels
/ metabolism
Zinc Finger E-box Binding Homeobox 2
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 11 2019
29 11 2019
Historique:
received:
08
03
2019
accepted:
24
10
2019
entrez:
1
12
2019
pubmed:
1
12
2019
medline:
15
12
2020
Statut:
epublish
Résumé
Podocytes are specialized cells of the glomerulus and key component of the glomerular filtration apparatus (GFA). GFA regulates the permselectivity and ultrafiltration of blood. The mechanism by which the integrity of the GFA is compromised and manifest in proteinuria during ischemic stroke remains enigmatic. We investigated the mechanism of ischemic hypoxia-induced proteinuria in a middle cerebral artery occlusion (MCAO) model. Ischemic hypoxia resulted in the accumulation of HIF1α in the podocytes that resulted in the increased expression of ZEB2 (Zinc finger E-box-binding homeobox 2). ZEB2, in turn, induced TRPC6 (transient receptor potential cation channel, subfamily C, member 6), which has increased selectivity for calcium. Elevated expression of TRPC6 elicited increased calcium influx and aberrant activation of focal adhesion kinase (FAK) in podocytes. FAK activation resulted in the stress fibers reorganization and podocyte foot process effacement. Our study suggests overactive HIF1α/ZEB2 axis during ischemic-hypoxia raises intracellular calcium levels via TRPC6 and consequently altered podocyte structure and function thus contributes to proteinuria.
Identifiants
pubmed: 31784544
doi: 10.1038/s41598-019-52872-5
pii: 10.1038/s41598-019-52872-5
pmc: PMC6884642
doi:
Substances chimiques
Calcium Channel Blockers
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
TRPC Cation Channels
0
Trpc6 protein, rat
0
Zeb2 protein, rat
0
Zinc Finger E-box Binding Homeobox 2
0
Focal Adhesion Protein-Tyrosine Kinases
EC 2.7.10.2
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
17897Références
J Cell Biol. 2007 Feb 26;176(5):667-80
pubmed: 17325207
Am J Nephrol. 2016;44(4):276-285
pubmed: 27607351
Science. 2005 Jun 17;308(5729):1801-4
pubmed: 15879175
Cell Signal. 2005 Apr;17(4):437-45
pubmed: 15601622
Stroke. 2002 Jun;33(6):1630-5
pubmed: 12053003
Clin Exp Pharmacol Physiol. 2011 Jul;38(7):474-80
pubmed: 21545630
Cell Calcium. 2011 Dec;50(6):523-9
pubmed: 21959089
Clin Med Res. 2016 Mar;14(1):15-39
pubmed: 26847481
Nephrol Dial Transplant. 2014 Mar;29(3):497-506
pubmed: 23525530
Mech Dev. 2014 Feb;131:86-110
pubmed: 24161570
Stroke. 2004 Aug;35(8):1979-84
pubmed: 15205492
Kidney Int. 2006 Jun;69(11):2101-6
pubmed: 16625147
J Cell Physiol. 2019 May;234(5):6503-6518
pubmed: 30238984
Arch Biochem Biophys. 2016 Jan 15;590:10-19
pubmed: 26550927
Front Endocrinol (Lausanne). 2014 Sep 25;5:151
pubmed: 25309512
Drugs Aging. 1994 Oct;5(4):263-87
pubmed: 7827397
Brain Res. 2002 Nov 15;955(1-2):85-97
pubmed: 12419524
Annu Rev Med. 1990;41:289-302
pubmed: 2184731
Am J Kidney Dis. 2003 Jan;41(1):1-12
pubmed: 12500213
Kidney Int Suppl. 2005 Dec;(99):S46-51
pubmed: 16336576
Exp Transl Stroke Med. 2016 Dec 7;8:9
pubmed: 27980710
BMC Med. 2011 Feb 02;9:11
pubmed: 21288330
Am J Pathol. 2004 Dec;165(6):1979-92
pubmed: 15579441
J Cell Biochem. 2015 Sep;116(9):1947-56
pubmed: 25740786
Development. 2005 Oct;132(20):4437-48
pubmed: 16162653
Trends Cell Biol. 2007 Sep;17(9):428-37
pubmed: 17804239
Stroke. 2009 Apr;40(4):1296-303
pubmed: 19182072
J Biol Chem. 2005 Dec 2;280(48):39786-94
pubmed: 16204251
J Biol Chem. 2010 Oct 8;285(41):31148-56
pubmed: 20682777
Pharmacol Rev. 2014 Jul;66(3):676-814
pubmed: 24951385
Am J Physiol Renal Physiol. 2015 Sep 1;309(5):F393-7
pubmed: 26084930
J Cell Sci. 2007 Oct 15;120(Pt 20):3491-9
pubmed: 17928305
J Cell Biochem. 2018 Nov 1;:
pubmed: 30387200
J Am Soc Nephrol. 2010 Jul;21(7):1145-56
pubmed: 20522532
Nat Genet. 2005 Jul;37(7):739-44
pubmed: 15924139
Kidney Int Suppl. 2000 Apr;75:S22-6
pubmed: 10828757
J Stroke. 2015 Jan;17(1):54-9
pubmed: 25692107
Neurology. 2012 Jun 12;78(24):1909-15
pubmed: 22592359
Cell Mol Life Sci. 2009 Mar;66(5):773-87
pubmed: 19011757
J Hypertens. 2006 Mar;24(3):535-9
pubmed: 16467657
J Am Soc Nephrol. 2013 Mar;24(4):537-41
pubmed: 23334390
Stroke. 2015 Aug;46(8):2075-80
pubmed: 26130097
J Biol Chem. 2004 Jul 2;279(27):28715-23
pubmed: 15102844
Hypertension. 2013 Nov;62(5):914-9
pubmed: 24019401
Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5192-6
pubmed: 1594631
Toxicol Appl Pharmacol. 2008 Sep 15;231(3):291-9
pubmed: 18597805
Kidney Int. 2017 Apr;91(4):830-841
pubmed: 27979597
Nephrol Dial Transplant. 2009 Jan;24(1):194-200
pubmed: 18728156
Curr Hypertens Rep. 2010 Oct;12(5):378-83
pubmed: 20676805
J Clin Anesth. 2000 Sep;12(6):421-6
pubmed: 11090726
Am J Physiol Renal Physiol. 2013 Jan 1;304(1):F127-36
pubmed: 23019228
Clin Exp Pharmacol Physiol. 2013 Feb;40(2):123-37
pubmed: 23181475
Clin Exp Pharmacol Physiol. 2013 Feb;40(2):138-47
pubmed: 23360244
Nephrol Dial Transplant. 2016 Oct;31(10):1577-83
pubmed: 26968197
J Neurointerv Surg. 2017 May;9(5):445-448
pubmed: 27106594
Am J Physiol Renal Physiol. 2016 May 1;310(9):F807-9
pubmed: 26936871
Brain Res. 1999 Jul 3;833(2):181-90
pubmed: 10375693
J Cell Sci. 2000 Oct;113 ( Pt 20):3673-8
pubmed: 11017882
Dev Cell. 2012 Oct 16;23(4):705-15
pubmed: 23022034