Stabilization of hypoxia-inducible factor ameliorates glomerular injury sensitization after tubulointerstitial injury.
HIF
dimethyloxalylglycine
glomerulosclerosis
interstitial fibrosis
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
04
09
2019
revised:
14
09
2020
accepted:
17
09
2020
pubmed:
3
11
2020
medline:
22
6
2021
entrez:
2
11
2020
Statut:
ppublish
Résumé
Previously, we found that mild tubulointerstitial injury sensitizes glomeruli to subsequent injury. Here, we evaluated whether stabilization of hypoxia-inducible factor-α (HIF-α), a key regulator of tissue response to hypoxia, ameliorates tubulointerstitial injury and impact on subsequent glomerular injury. Nep25 mice, which express the human CD25 receptor on podocytes under control of the nephrin promotor and develop glomerulosclerosis when a specific toxin is administered were used. Tubulointerstitial injury, evident by week two, was induced by folic acid, and mice were treated with an HIF stabilizer, dimethyloxalylglycine or vehicle from week three to six. Uninephrectomy at week six assessed tubulointerstitial fibrosis. Glomerular injury was induced by podocyte toxin at week seven, and mice were sacrificed ten days later. At week six tubular injury markers normalized but with patchy collagen I and interstitial fibrosis. Pimonidazole staining, a hypoxia marker, was increased by folic acid treatment compared to vehicle while dimethyloxalylglycine stimulated HIF-2α expression and attenuated tubulointerstitial hypoxia. The hematocrit was increased by dimethyloxalylglycine along with downstream effectors of HIF. Tubular epithelial cell injury, inflammation and interstitial fibrosis were improved after dimethyloxalylglycine, with further reduced mortality, interstitial fibrosis, and glomerulosclerosis induced by specific podocyte injury. Thus, our findings indicate that hypoxia contributes to tubular injury and consequent sensitization of glomeruli to injury. Hence, restoring HIFs may blunt this adverse crosstalk of tubules to glomeruli.
Identifiants
pubmed: 33137336
pii: S0085-2538(20)31240-0
doi: 10.1016/j.kint.2020.09.031
pmc: PMC7914150
mid: NIHMS1644757
pii:
doi:
Substances chimiques
Hypoxia-Inducible Factor 1, alpha Subunit
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
620-631Subventions
Organisme : BLRD VA
ID : I01 BX002348
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK056942
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK081646
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101791
Pays : United States
Informations de copyright
Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Références
Am J Physiol Renal Physiol. 2006 Aug;291(2):F271-81
pubmed: 16554418
Nature. 2008 Jun 5;453(7196):807-11
pubmed: 18432192
N Engl J Med. 2014 Jul 3;371(1):58-66
pubmed: 24988558
Am J Pathol. 2003 Dec;163(6):2289-301
pubmed: 14633603
Kidney Int. 2012 Jul;82(2):128-30
pubmed: 22743562
Kidney Int. 2012 Mar;81(5):442-8
pubmed: 22113526
Front Physiol. 2017 Jan 05;7:667
pubmed: 28105019
Curr Opin Anaesthesiol. 2017 Feb;30(1):100-104
pubmed: 27977430
Am J Kidney Dis. 1992 Jul;20(1):1-17
pubmed: 1621674
Am J Physiol Renal Physiol. 2013 Nov 1;305(9):F1323-31
pubmed: 23946285
Am J Physiol Renal Physiol. 2012 May 1;302(9):F1172-9
pubmed: 22262480
Nat Rev Nephrol. 2016 Mar;12(3):157-68
pubmed: 26656456
Pediatr Nephrol. 2012 Jun;27(6):901-9
pubmed: 21947270
J Clin Invest. 2007 Dec;117(12):3810-20
pubmed: 18037992
J Am Soc Nephrol. 2008 Jan;19(1):39-46
pubmed: 18178798
Kidney Int. 2016 Oct;90(4):797-808
pubmed: 27503806
J Clin Invest. 2016 Apr 1;126(4):1425-37
pubmed: 26927670
FASEB J. 2020 Feb;34(2):2344-2358
pubmed: 31908020
Am J Physiol Renal Physiol. 2003 Feb;284(2):F338-48
pubmed: 12388385
Kidney Int Suppl (2011). 2014 Nov;4(1):84-90
pubmed: 26312156
Am J Physiol Renal Physiol. 2017 Aug 1;313(2):F282-F290
pubmed: 28331062
Nephrol Ther. 2016 Apr;12 Suppl 1:S41-8
pubmed: 26972097
N Engl J Med. 1995 Mar 9;332(10):647-55
pubmed: 7845430
Kidney Int. 2008 Oct;74(7):867-72
pubmed: 18633339
Am J Surg. 2000 Aug;180(2):108-14
pubmed: 11044523
Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
pubmed: 7539918
J Clin Invest. 2014 Jun;124(6):2396-409
pubmed: 24789906
Ann N Y Acad Sci. 2009 Oct;1177:57-65
pubmed: 19845607
J Am Soc Nephrol. 2001 Dec;12(12):2721-31
pubmed: 11729241
Am J Physiol. 1998 Feb;274(2):L212-9
pubmed: 9486205
Nephrol Dial Transplant. 2017 Dec 1;32(12):2097-2105
pubmed: 27798200
Nephrol Dial Transplant. 2010 Jan;25(1):77-85
pubmed: 19737871
Mol Cell. 2008 May 23;30(4):393-402
pubmed: 18498744
Nat Rev Nephrol. 2015 May;11(5):264-76
pubmed: 25643664
J Am Soc Nephrol. 2015 Feb;26(2):328-38
pubmed: 25183809
Drug Discov Today Dis Models. 2014 Spring;11:45-51
pubmed: 25722733
J Am Soc Nephrol. 2002 Jul;13(7):1721-32
pubmed: 12089367
Int J Oral Sci. 2018 Apr 13;10(2):12
pubmed: 29654284
Kidney Int. 2008 Aug;74(4):495-504
pubmed: 18528327
PLoS One. 2012;7(11):e48952
pubmed: 23145036
Mol Cell. 2010 Oct 22;40(2):294-309
pubmed: 20965423
J Pharmacol Exp Ther. 2013 Dec;347(3):626-34
pubmed: 24042162
J Am Soc Nephrol. 2005 Apr;16(4):1013-23
pubmed: 15758046
JCI Insight. 2019 Dec 19;4(24):
pubmed: 31743113
Kidney Int. 2000 Dec;58(6):2351-66
pubmed: 11115069
J Am Soc Nephrol. 2006 Jan;17(1):17-25
pubmed: 16291837
Am J Physiol Renal Physiol. 2011 Mar;300(3):F792-800
pubmed: 21177778
Science. 2001 Apr 20;292(5516):468-72
pubmed: 11292861
Kidney Int. 2017 Dec;92(6):1395-1403
pubmed: 28709637
Kidney Int. 1997 Feb;51(2):372-80
pubmed: 9027709
J Am Soc Nephrol. 2006 Jul;17(7):1970-8
pubmed: 16762988
Mol Biol Cell. 2007 Dec;18(12):4691-7
pubmed: 17898080