Angiotensin II-Induced Hypertension Is Attenuated by Reduction of Sympathetic Output in NO-Sensitive Guanylyl Cyclase 1 Knockout Mice

Angiotensin II via type 1 receptor activation upregulates the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and LOX-1 activation, in turn, upregulates angiotensin II type 1 receptor expression. We postulated that interruption of this positive feedback loop might attenuate the genesis of angiotensin II–induced hypertension and subsequent cardiac remodeling. To examine this postulate, LOX-1 knockout and wild-type mice were infused with angiotensin II or norepinephrine (control for angiotensin II) for 4 weeks. Angiotensin II–, but not norepinephrine-, induced hypertension was attenuated in LOX-1 knockout mice. Angiotensin II–induced cardiac remodeling was also attenuated in LOX-1 knockout mice. Importantly, angiotensin II type 1 receptor expression was reduced, and the expression and activity of endothelial NO synthase were preserved in the tissues of LOX-1 knockout mice given angiotensin II. Reactive oxygen species generation, nicotinamide-adenine dinucleotide phosphate oxidase expression, and phosphorylation of p38 and p44/42 mitogen-activated protein kinases were also much less pronounced in the LOX-1 knockout mice given angiotensin II. These alterations in biochemical and structural abnormalities were associated with preservation of cardiac hemodynamics in the LOX-1 knockout mice. To confirm that fibroblast function is modulated in the absence of LOX-1, cardiac fibroblasts from wild-type and LOX-1 knockout mice were treated with angiotensin II. Indeed, LOX-1 knockout mice cardiac fibroblasts revealed an attenuated profibrotic response on treatment with angiotensin II. These observations provide strong evidence that LOX-1 is a key modulator of the development of angiotensin II–induced hypertension and subsequent cardiac remodeling.

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NO resistance in angiotensin II–induced hypertension is associated with S-nitrosation of soluble guanylyl cyclase

BMC Pharmacology ◽

10.1186/1471-2210-11-s1-o33 ◽

2011 ◽

Vol 11 (S1) ◽

Author(s):

Pierre-Antoine Crassous ◽

Samba Couloubaly ◽

Padma Baskaran ◽

Zongmin Zhou ◽

Andreas Papapetropoulos ◽

...

Keyword(s):

Angiotensin Ii ◽

Guanylyl Cyclase ◽

Soluble Guanylyl Cyclase ◽

Induced Hypertension

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Angiotensin-II induced hypertension and renovascular remodelling in tissue inhibitor of metalloproteinase 2 knockout mice

Journal of Hypertension ◽

10.1097/hjh.0b013e3283649b33 ◽

2013 ◽

Vol 31 (11) ◽

pp. 2270-2281 ◽

Cited By ~ 23

Author(s):

Sathnur Pushpakumar ◽

Sourav Kundu ◽

Tyranny Pryor ◽

Srikanth Givvimani ◽

Eleanor Lederer ◽

...

Keyword(s):

Angiotensin Ii ◽

Knockout Mice ◽

Tissue Inhibitor Of Metalloproteinase ◽

Tissue Inhibitor ◽

Induced Hypertension

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A new mechanism for the sex differences in angiotensin II-induced hypertension: the role of macula densa NOS1β-mediated tubuloglomerular feedback

AJP Renal Physiology ◽

10.1152/ajprenal.00312.2020 ◽

2020 ◽

Vol 319 (5) ◽

pp. F908-F919

Author(s):

Jie Zhang ◽

Larry Qu ◽

Jin Wei ◽

Shan Jiang ◽

Lan Xu ◽

...

Keyword(s):

Sex Differences ◽

Angiotensin Ii ◽

Knockout Mice ◽

Macula Densa ◽

Tubuloglomerular Feedback ◽

Ang Ii ◽

Wild Type ◽

Induced Hypertension

Females are protected against the development of angiotensin II (ANG II)-induced hypertension compared with males, but the mechanisms have not been completely elucidated. In the present study, we hypothesized that the effect of ANG II on the macula densa nitric oxide (NO) synthase 1β (NOS1β)-mediated tubuloglomerular feedback (TGF) mechanism is different between males and females, thereby contributing to the sexual dimorphism of ANG II-induced hypertension. We used microperfusion, micropuncture, clearance of FITC-inulin, and radio telemetry to examine the sex differences in the changes of macula densa NOS1β expression and activity, TGF response, natriuresis, and blood pressure (BP) after a 2-wk ANG II infusion in wild-type and macula densa-specific NOS1 knockout mice. In wild-type mice, ANG II induced higher expression of macula densa NOS1β, greater NO generation by the macula densa, and a lower TGF response in vitro and in vivo in females than in males; the increases of glomerular filtration rate, urine flow rate, and Na+ excretion in response to an acute volume expansion were significantly greater and the BP responses to ANG II were significantly less in females than in males. In contrast, these sex differences in the effects of ANG II on TGF, natriuretic response, and BP were largely diminished in knockout mice. In addition, tissue culture of human kidney biopsies (renal cortex) with ANG II resulted in a greater increase in NOS1β expression in females than in males. In conclusion, macula densa NOS1β-mediated TGF is a novel and important mechanism for the sex differences in ANG II-induced hypertension.

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The Orphan Receptor GPR35 Contributes to Angiotensin II–Induced Hypertension and Cardiac Dysfunction in Mice

American Journal of Hypertension ◽

10.1093/ajh/hpy073 ◽

2018 ◽

Vol 31 (9) ◽

pp. 1049-1058 ◽

Cited By ~ 4

Author(s):

Nina Divorty ◽

Graeme Milligan ◽

Delyth Graham ◽

Stuart A Nicklin

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Cardiac Function ◽

Knockout Mice ◽

Messenger Rna ◽

Orphan Receptor ◽

Rna Expression ◽

Ang Ii ◽

Wild Type ◽

Induced Hypertension

Abstract BACKGROUND The orphan receptor G protein–coupled receptor 35 (GPR35) has been associated with a range of diseases, including cancer, inflammatory bowel disease, diabetes, hypertension, and heart failure. To assess the potential for GPR35 as a therapeutic target in cardiovascular disease, this study investigated the cardiovascular phenotype of a GPR35 knockout mouse under both basal conditions and following pathophysiological stimulation. METHODS Blood pressure was monitored in male wild-type and GPR35 knockout mice over 7–14 days using implantable telemetry. Cardiac function and dimensions were assessed using echocardiography, and cardiomyocyte morphology evaluated histologically. Two weeks of angiotensin II (Ang II) infusion was used to investigate the effects of GPR35 deficiency under pathophysiological conditions. Gpr35 messenger RNA expression in cardiovascular tissues was assessed using quantitative polymerase chain reaction. RESULTS There were no significant differences in blood pressure, cardiac function, or cardiomyocyte morphology in GPR35 knockout mice compared with wild-type mice. Following Ang II infusion, GPR35 knockout mice were protected from significant increases in systolic, diastolic, and mean arterial blood pressure or impaired left ventricular systolic function, in contrast to wild-type mice. There were no significant differences in Gpr35 messenger RNA expression in heart, kidney, and aorta following Ang II infusion in wild-type mice. CONCLUSIONS Although GPR35 does not appear to influence basal cardiovascular regulation, these findings demonstrate that it plays an important pathological role in the development of Ang II–induced hypertension and impaired cardiac function. This suggests that GPR35 is a potential novel drug target for therapeutic intervention in hypertension.

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