Augmenting Renal Lymphatic Density Prevents Angiotensin II-Induced Hypertension in Male and Female Mice.
Angiotensin II
Animals
Blood Pressure
Cells, Cultured
Disease Models, Animal
Endothelial Cells
/ metabolism
Female
Hypertension
/ chemically induced
Kidney
/ metabolism
Lymphangiogenesis
Lymphatic Vessels
/ metabolism
Macrophages, Peritoneal
/ metabolism
Male
Mice, Inbred C57BL
Mice, Transgenic
Spleen
/ metabolism
Vascular Endothelial Growth Factor D
/ genetics
angiotensin II
blood pressure
hypertension
immunity
kidney
lymphatics
Journal
American journal of hypertension
ISSN: 1941-7225
Titre abrégé: Am J Hypertens
Pays: United States
ID NLM: 8803676
Informations de publication
Date de publication:
01 01 2020
01 01 2020
Historique:
received:
24
05
2019
revised:
31
07
2019
accepted:
15
08
2019
pubmed:
21
8
2019
medline:
22
12
2020
entrez:
21
8
2019
Statut:
ppublish
Résumé
Renal inflammation and immune cell infiltration are characteristic of several forms of hypertension. Our laboratory has previously demonstrated that renal-inflammation-associated lymphangiogenesis occurs in salt-sensitive and nitric-oxide-inhibition-induced hypertension. Moreover, enhancing renal lymphatic density prevented the development of these two forms of hypertension. Here, we investigated the effects of angiotensin II-induced hypertension on renal lymphatic vessel density in male and female mice. Wild-type and genetically engineered male and female mice were infused with angiotensin II for 2 or 3 weeks. Isolated splenocytes and peritoneal macrophages from mice, and commercially available mouse lymphatic endothelial cells were used for in vitro studies. Compared to vehicle controls, angiotensin II-infused male and female mice had significantly increased renal lymphatic vessel density in association with pro-inflammatory immune cells in the kidneys of these mice. Direct treatment of lymphatic endothelial cells with angiotensin II had no effect as they lack angiotensin II receptors; however, angiotensin II treatment of splenocytes and peritoneal macrophages induced secretion of the lymphangiogenic growth factor VEGF-C in vitro. Utilizing our genetic mouse model of inducible renal lymphangiogenesis, we demonstrated that greatly augmenting renal lymphatic density prior to angiotensin II infusion prevented the development of hypertension in male and female mice and this was associated with a reduction in renal CD11c+F4/80- monocytes. Renal lymphatics play a significant role in renal immune cell trafficking and blood pressure regulation, and represent a novel avenue of therapy for hypertension.
Sections du résumé
BACKGROUND
Renal inflammation and immune cell infiltration are characteristic of several forms of hypertension. Our laboratory has previously demonstrated that renal-inflammation-associated lymphangiogenesis occurs in salt-sensitive and nitric-oxide-inhibition-induced hypertension. Moreover, enhancing renal lymphatic density prevented the development of these two forms of hypertension. Here, we investigated the effects of angiotensin II-induced hypertension on renal lymphatic vessel density in male and female mice.
METHODS
Wild-type and genetically engineered male and female mice were infused with angiotensin II for 2 or 3 weeks. Isolated splenocytes and peritoneal macrophages from mice, and commercially available mouse lymphatic endothelial cells were used for in vitro studies.
RESULTS
Compared to vehicle controls, angiotensin II-infused male and female mice had significantly increased renal lymphatic vessel density in association with pro-inflammatory immune cells in the kidneys of these mice. Direct treatment of lymphatic endothelial cells with angiotensin II had no effect as they lack angiotensin II receptors; however, angiotensin II treatment of splenocytes and peritoneal macrophages induced secretion of the lymphangiogenic growth factor VEGF-C in vitro. Utilizing our genetic mouse model of inducible renal lymphangiogenesis, we demonstrated that greatly augmenting renal lymphatic density prior to angiotensin II infusion prevented the development of hypertension in male and female mice and this was associated with a reduction in renal CD11c+F4/80- monocytes.
CONCLUSION
Renal lymphatics play a significant role in renal immune cell trafficking and blood pressure regulation, and represent a novel avenue of therapy for hypertension.
Identifiants
pubmed: 31429865
pii: 5552131
doi: 10.1093/ajh/hpz139
pmc: PMC6931897
doi:
Substances chimiques
Vascular Endothelial Growth Factor D
0
Vegfd protein, mouse
0
Angiotensin II
11128-99-7
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
61-69Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK120493
Pays : United States
Informations de copyright
© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Am J Hypertens. 2018 Nov 13;31(12):1247-1254
pubmed: 30299518
J Am Soc Nephrol. 2004 Mar;15(3):603-12
pubmed: 14978162
Am J Physiol Heart Circ Physiol. 2016 Aug 1;311(2):H384-94
pubmed: 27342876
Kidney Int. 2012 May;81(9):865-79
pubmed: 22258325
Circulation. 2016 Jan 26;133(4):e38-360
pubmed: 26673558
Curr Hypertens Rep. 2018 Oct 5;20(12):100
pubmed: 30291560
N Engl J Med. 1977 Mar 24;296(12):641-6
pubmed: 190537
Cell Rep. 2017 Oct 24;21(4):1009-1020
pubmed: 29069584
Kidney Int. 2013 Jan;83(1):50-62
pubmed: 22932121
Am J Physiol Renal Physiol. 2017 Aug 1;313(2):F141-F144
pubmed: 28404590
Br J Pharmacol. 2019 Jun;176(12):1978-1988
pubmed: 29797446
Clin J Am Soc Nephrol. 2017 Mar 7;12(3):524-535
pubmed: 27895136
Am J Physiol Renal Physiol. 2017 May 1;312(5):F861-F869
pubmed: 28228406
Arterioscler Thromb Vasc Biol. 2018 Jun;38(6):1346-1357
pubmed: 29650694
Hypertension. 2017 Dec;70(6):1219-1227
pubmed: 29061720
J Clin Invest. 1999 Dec;104(12):1693-701
pubmed: 10606623
FEBS Lett. 1994 Jun 27;347(2-3):178-80
pubmed: 7518396
Hypertension. 2014 Aug;64(2):384-390
pubmed: 24890822
Hypertension. 2002 Feb;39(2 Pt 2):316-22
pubmed: 11882566
Circ Res. 2018 Apr 13;122(8):1094-1101
pubmed: 29475981
J Histochem Cytochem. 2007 Jul;55(7):721-33
pubmed: 17371935
J Exp Med. 2007 Oct 1;204(10):2449-60
pubmed: 17875676
Blood. 2011 Apr 28;117(17):4667-78
pubmed: 21364190
Exp Biol Med (Maywood). 2017 Apr;242(8):884-895
pubmed: 28346012
Hypertension. 2015 Nov;66(5):1023-33
pubmed: 26351030
Hypertension. 2018 Jun;71(6):1269-1324
pubmed: 29133354
Expert Rev Mol Med. 2014 Sep 25;16:e15
pubmed: 25252809
Am J Pathol. 1958 Jul-Aug;34(4):685-715
pubmed: 13559400
Am J Physiol Regul Integr Comp Physiol. 2010 Apr;298(4):R1136-42
pubmed: 20147611
Hypertension. 2015 Jan;65(1):54-61
pubmed: 25399687
J Exp Med. 2006 Nov 27;203(12):2763-77
pubmed: 17116732
Arch Intern Med (Chic). 1947 Oct;80(4):454-62
pubmed: 20269267
Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2106-13
pubmed: 16100037
Hypertension. 2014 Sep;64(3):573-82
pubmed: 24935938