Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease.
Animals
Atherosclerosis
/ complications
Disease Models, Animal
Elastin
/ administration & dosage
Female
Glomerular Filtration Rate
/ drug effects
Humans
Kidney
/ blood supply
Male
Microvessels
/ drug effects
Peptides
/ administration & dosage
Recombinant Fusion Proteins
/ administration & dosage
Recovery of Function
/ drug effects
Renal Artery Obstruction
/ drug therapy
Renal Circulation
/ drug effects
Sus scrofa
Vascular Endothelial Growth Factor A
/ administration & dosage
Angiogenesis
Drug-delivery technology
Macrophage
Microcirculation
Renovascular disease
Vascular endothelial growth factor
Journal
American journal of nephrology
ISSN: 1421-9670
Titre abrégé: Am J Nephrol
Pays: Switzerland
ID NLM: 8109361
Informations de publication
Date de publication:
2020
2020
Historique:
received:
11
06
2020
accepted:
31
08
2020
pubmed:
2
11
2020
medline:
14
9
2021
entrez:
1
11
2020
Statut:
ppublish
Résumé
Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery. Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR). Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment. Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.
Sections du résumé
BACKGROUND
Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery.
METHODS
Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR).
RESULTS
Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment.
CONCLUSIONS
Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.
Identifiants
pubmed: 33130676
pii: 000511260
doi: 10.1159/000511260
pmc: PMC7750286
mid: NIHMS1633333
doi:
Substances chimiques
Peptides
0
Recombinant Fusion Proteins
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
Elastin
9007-58-3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
891-902Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL051971
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM104357
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL095638
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL121527
Pays : United States
Informations de copyright
© 2020 S. Karger AG, Basel.
Références
Kidney Int. 2005 Jul;68(1):293-301
pubmed: 15954920
Kidney Int. 2018 Apr;93(4):842-854
pubmed: 29273331
Biochem Biophys Res Commun. 2005 Jun 24;332(1):11-6
pubmed: 15896292
Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):E944-53
pubmed: 22451944
Am J Hypertens. 2018 Jan 12;31(2):139-149
pubmed: 28985335
Biomed Pharmacother. 2019 Jan;109:408-416
pubmed: 30399576
Am J Physiol Renal Physiol. 2012 May 15;302(10):F1342-50
pubmed: 22357917
J Am Soc Nephrol. 2015 Apr;26(4):817-29
pubmed: 25535303
J Am Soc Nephrol. 2016 Jun;27(6):1741-52
pubmed: 26541349
Cell Signal. 2007 Oct;19(10):2003-12
pubmed: 17658244
PLoS One. 2018 Jan 11;13(1):e0191040
pubmed: 29324807
Nature. 1996 Mar 28;380(6572):364-6
pubmed: 8598934
Am J Physiol Renal Physiol. 2011 Jul;301(1):F218-25
pubmed: 21478482
Hypertension. 2019 Nov;74(5):1113-1123
pubmed: 31542966
N Engl J Med. 2009 Nov 12;361(20):1953-62
pubmed: 19907042
Am J Pathol. 2004 May;164(5):1531-5
pubmed: 15111299
Arterioscler Thromb Vasc Biol. 2013 May;33(5):1006-13
pubmed: 23430615
Nephrol Dial Transplant. 2010 Apr;25(4):1079-87
pubmed: 19934087
J Am Soc Nephrol. 1999 Jul;10(7):1455-65
pubmed: 10405201
Microcirculation. 2010 May;17(4):250-8
pubmed: 20536738
Hypertension. 2020 Jan;75(1):193-201
pubmed: 31786977
Biochem Pharmacol. 2007 Mar 1;73(5):620-31
pubmed: 17161827
Mol Cancer Ther. 2005 Jul;4(7):1076-85
pubmed: 16020665
Int J Nephrol Renovasc Dis. 2014 Feb 18;7:75-88
pubmed: 24600241
Pharmaceutics. 2019 Oct 18;11(10):
pubmed: 31635263
Reprod Sci. 2009 Oct;16(10):970-9
pubmed: 19528353
Rom J Morphol Embryol. 2018;59(2):455-467
pubmed: 30173249
Ren Fail. 2012;34(1):126-9
pubmed: 22010784
Kidney Int. 2015 Feb;87(2):297-307
pubmed: 25162398
Nephron Exp Nephrol. 2008;110(3):e73-81
pubmed: 18953181
FASEB J. 2006 Aug;20(10):1706-8
pubmed: 16790524
Biomaterials. 2014 May;35(15):4477-88
pubmed: 24589361
Drug Dev Ind Pharm. 1999 May;25(5):591-6
pubmed: 10219527
Am J Physiol Renal Physiol. 2020 Jul 1;319(1):F139-F148
pubmed: 32538151
Circ Cardiovasc Interv. 2010 Aug;3(4):376-83
pubmed: 20587789
PLoS One. 2010 Jan 13;5(1):e8668
pubmed: 20084270
Diabetes. 2012 Nov;61(11):2958-66
pubmed: 23093658
Am J Physiol Renal Physiol. 2017 Jan 1;312(1):F54-F64
pubmed: 27784692
Am J Physiol Renal Physiol. 2018 Aug 1;315(2):F364-F373
pubmed: 29693449
Am J Physiol Renal Physiol. 2008 Dec;295(6):F1648-57
pubmed: 18799550
Circulation. 2002 Aug 27;106(9):1165-71
pubmed: 12196346
Kidney Int. 2014 Apr;85(4):833-44
pubmed: 24352153
Invest New Drugs. 2007 Aug;25(4):313-26
pubmed: 17483874
J Immunol. 2000 Jun 15;164(12):6166-73
pubmed: 10843666
Int J Oncol. 2019 Jul;55(1):103-115
pubmed: 31115579
Kidney Int. 2012 Oct;82(8):928-33
pubmed: 22673886
Endocrinol Metab Clin North Am. 2019 Dec;48(4):765-778
pubmed: 31655775
J Immunol. 2012 Apr 1;188(7):3382-94
pubmed: 22393154
Am J Physiol Renal Physiol. 2019 May 1;316(5):F1016-F1025
pubmed: 30892933