Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice

2008 ◽  
Vol 294 (1) ◽  
pp. F120-F129 ◽  
Author(s):  
Frédéric Michel ◽  
Serge Simonet ◽  
Christine Vayssettes-Courchay ◽  
Florence Bertin ◽  
Patricia Sansilvestri-Morel ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Kidney Disease ◽  
Renal Diseases ◽  
Receptor Ligands ◽  
Tp Receptor ◽  
Vasodilator Activity ◽  
Tp Receptors ◽  
Apoe Ko Mice ◽  
Apoe Ko ◽  
Biphasic Responses

Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A2) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH2, and 8-iso-PGF2α, but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF2α were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.

Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

2002 ◽  
Vol 11 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Doris M. Tham ◽  
Baby Martin-McNulty ◽  
Yi-xin Wang ◽  
Dennis W. Wilson ◽  
Ronald Vergona ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Aortic Aneurysms ◽  
Intercellular Adhesion Molecule ◽  
Ang Ii ◽  
Inflammatory Genes ◽  
Apoe Ko Mice ◽  
Apoe Ko

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-κB (NF-κB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-κB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-α and PPAR-γ mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-κB with increases in both p52 and p65 NF-κB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-κB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-α and -γ by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.

Abstract 520: Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling and Sudden Death

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Matthew A Sparks ◽  
Natalia Makhanova ◽  
Robert C Griffiths ◽  
John N Snouwaert ◽  
Beverly Koller ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Sudden Death ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Muscle Cells ◽  
Link Type ◽  
Tp Receptor ◽  
Induced Hypertension ◽  
Tp Receptors

The prostanoid thromboxane (TxA2) is a potent vasoconstrictor and platelet aggregant that has been implicated in the pathogenesis of cardiovascular diseases including hypertension. Actions of thromboxane (TP) receptors in platelets and the vasculature have both been implicated in cardiovascular pathogenesis. To distinguish the contributions of vascular TP receptors in isolation, we generated mice with cell-specific deletion of TP receptors in smooth muscle cells (TP-SMKOs) using Cre/Loxp technology. We used the KISM22α-Cre transgenic mouse line, with Cre recombinase “knocked-in” to the Sm22α gene locus, to excise the conditional Tp receptor allele specifically in smooth muscle. mRNA for the TP-receptor was easily detected in aortae from control mice, but not from TP-SMKOs (P<0.005). Similarly, TP receptor mRNA expression in mesenteric arteries, with intact endothelium and adventitia, was decreased by ≈80% in TP-SMKOs (P=0.05). In TP-SMKOs, acute vasoconstrictor responses to the TP agonist U46619 were dramatically attenuated by ≈60% in both the peripheral and renal circulations (P<0.05), whereas acute vascular responses to angiotensin II were unaffected. Infusion of high-dose U46619 caused circulatory collapse and death in a majority of control mice, but TP-SMKOs were completely protected from U46619 -induced sudden death (P<0.05). Baseline blood pressures measured by radiotelemetry were similar in TP-SMKOs (111±1 mmHg) and Controls (114±1 mmHg; P=NS). However, the absence of TP receptors in vascular smooth muscle cells caused significant attenuation of angiotensin II-induced hypertension (controls: 159±2 mm Hg; TP-SMKO: 145±8 mm Hg, P<0.05) and diminished aortic medial hypertrophy in TP-SMKOs (59±4 μm) vs. Controls (79±7 μm; P<0.05). Thus, vascular TP receptors play a major role in shock, angiotensin II-induced hypertension, and vascular remodeling.

Abstract 1311: Bone Marrow Angiotensin II Type 1 Receptor Augments Atherosclerosis by Promoting Monocyte/Macrophage Lineage Differentiation from Hematopoietic Stem Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yoshinori Tsubakimoto ◽  
Hiroyuki Yamada ◽  
Hirokazu Yokoi ◽  
Hiroki Takata ◽  
Hiroyuki Kawahito ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Hematopoietic Stem Cells ◽  
Atherosclerotic Lesion ◽  
Ang Ii ◽  
Hematopoietic Stem ◽  
Apoe Ko Mice ◽  
Apoe Ko

[BACKGROUND] The angiotensin II (Ang II) type 1 (AT 1 ) receptor is crucially involved in atherogenesis, but bone marrow (BM) AT 1 -mediated proatherogenic action remains undefined- . [METHOD AND RESULT] BM-derived mononuclear cells (BM-MNCs) more abundantly express AT 1 than VSMCs (2.2 fold) with similar affinities to Ang II. BM cells in 8-week-old apoE-deficient −/− ) or wild-type (Agtr1 + / + ) cells. Four (apoE-KO) mice were replaced with AT 1 -deficient (Agtr1 weeks after the initiation of western diet and Ang II infusion (500ng/kg/min), atherosclerotic lesion area in aortic root was examined. ApoE-KO mice reconstituted with Agtr1 −/− marrow (apoE-KO/BM-Agtr1 −/− ) showed a significant reduction in atherosclerotic lesions compared with apoE-KO/BM-Agtr1 + / + mice (55%, P <0.05). The accumulation of macrophages was attenuated in apoE-KO/BM-Agtr1 −/− mice (55%, P <0.05), concomitant with a decrease in the number of circulating Ly-6C hi monocytes (76%, P <0.01). The numbers of circulating CCR2 + and CX3CR1 + monocytes were also reduced in apoE-KO/BM-Agtr1 −/− mice (87±16 vs 298±66; CCR2 + monocyte, 72±12 vs 550±119 cells/μl; CX3CR1 + monocyte, respectively, P <0.01). Furthermore, the number of macrophage progenitor cells defined by M-CSF stimulated macrophage colony-forming unit was markedly reduced by 82 % (p<0.01) in Agtr1 −/− compared with Agtr1 + / + mice. We next examined the effect of BM-AT 1 on the number of hematopoietic stem cells (HSCs), common myeloid progenitors (CMP), and granulocyte/macrophage progenitors (GMP) to determine at which point of the lineage pathway, BM-AT 1 is involved. The number of HSCs did not differ between the two groups (3.6±0.8 vs 2.9±0.6 × 10 3 cells/tibia, P =n.s.), whereas the numbers of CMP and GMP were much lower in apoE-KO/BM-Agtr1 −/− mice (4.7±0.7 vs 10.2±1.4 ×10 3 cells/tibia, 9.9±2.7 vs 20.2±2.8 × 10 3 cells/tibia, respectively, P <0.05). [CONCLUSION] BM-MNCs expressed the abundant densities of AT1, and AT1-mediated signals on BM-MNCs exaggerated atherosclerotic lesion development. BM-AT 1 is closely implicated in the differentiation of HSCs into macrophage progenitors and the behavior of monocytes/macrophages, indicating that BM-AT 1 could be a promising therapeutic target for the prevention of cardiovascular events.

Role of thromboxane receptors in the dipsogenic response to central angiotensin II

2002 ◽  
Vol 282 (3) ◽  
pp. R865-R869 ◽  
Author(s):  
Chagriya Kitiyakara ◽  
William J. Welch ◽  
Joseph G. Verbalis ◽  
Christopher S. Wilcox
Keyword(s):  
Angiotensin Ii ◽  
Water Intake ◽  
Ang Ii ◽  
Tp Receptor ◽  
Drinking Response ◽  
Tp Receptors ◽  
Thromboxane Receptors ◽  
Prostaglandin H ◽  
The Brain

Central angiotensin II (ANG II) regulates thirst. Because thromboxane A2-prostaglandin H2 (TP) receptors are expressed in the brain and mediate some of the effects of ANG II in the vasculature, we investigated the hypothesis that TP receptors mediate the drinking response to intracerebroventricular (icv) injections of ANG II. Pretreatment with the specific TP-receptor antagonist ifetroban (Ifet) decreased water intake with 50 ng/kg icv ANG II (ANG II + Veh, 7.2 ± 0.7 ml vs. ANG II + Ifet, 2.8 ± 0.8 ml; n = 5 rats; P < 0.001) but had no effect on water intake induced by hypertonic saline (NaCl + Veh, 8.4 ± 1.1 ml vs. NaCl + Ifet, 8.9 ± 1.8 ml; n = 5 rats; P = not significant). Administration of 0.6 μg/kg icv of the TP-receptor agonist U-46,619 did not induce drinking when given alone but did increase the dipsogenic response to a near-threshold dose of 15 ng/kg icv ANG II (ANG II + Veh, 1.1 ± 0.7 vs. ANG II + U-46,619, 4.5 ± 0.9 ml; n = 5 rats; P < 0.01). We conclude that central TP receptors contribute to the dipsogenic response to ANG II.

1440Anti-inflammatory adipokine, omentin, attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein-E knockout mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Fang ◽  
K Ohashi ◽  
N Otaka ◽  
H Kawanishi ◽  
T Takikawa ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Inflammatory Response ◽  
Apolipoprotein E ◽  
Human Macrophages ◽  
Abdominal Aortic ◽  
Apo E ◽  
Apoe Ko Mice ◽  
Apoe Ko

Abstract Background Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity is associated with an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated by obesity. Recently we have demonstrated that omentin is an anti-inflammatory adipokine that prevents the development of atherosclerosis in apolipoprotein-E knockout (apoE-KO) mice. Here we examined whether omentin could modulate angiotensin II-induced AAA formation in apoE-KO mice. Methods and results To overexpress human omentin in apoE-KO mice, apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue under the control of AP2 promoter (OMT-Tg mice). Circulating levels of human omentin in apoE-KO/OMT-Tg mice were approximately threefold higher than those in healthy human subjects, whereas human omentin was undetectable in apoE-KO mice. There were no differences in body weight, blood pressure and heart rate between apoE-KO/OMT-Tg and apoE-KO mice. We also subjected apoE-KO/OMT-Tg and apoE-KO mice at 24 weeks of age to continuous angiotensin II-infusion by using osmotic mini pumps for 4 weeks, which is a widely-accepted model of experimental AAA. ApoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA determined by direct measurement and ultrasound imaging as compared with apo-E KO mice. In histological analyses with van Gieson staining, apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibers in response to angiotensin II compared with apo-E KO mice. ApoE-KO/OMT-Tg mice also displayed reduced mRNA levels of matrix metalloproteinase (MMP) 2 and MMP9 as well as pro-inflammation genes including interleukin (IL)-6 in aortic walls compared with apo-E KO mice. Treatment of human monocyte-derived macrophages with human omentin protein attenuated LPS-stimulated expression of MMP9, TNF-α and IL-6. Omentin treatment also reduced LPS-induced activation of MMP9 in cultured media of human macrophages as evaluated by gelatinolytic zymography. Omentin treatment increased phosphorylation levels of Akt in human macrophages. The suppressive effects of omentin on inflammatory response in macrophages were reversed by treatment with LY294002, which is an inhibitor of PI3 kinase/Akt signaling. Conclusion These data suggest that omentin acts as an adipokine that can attenuate angiotensin II-induced development of AAA through suppression of MMP activation and inflammatory response in the vascular wall.

Integrin-linked kinase plays a key role in the regulation of angiotensin II-induced renal inflammation

2014 ◽  
Vol 127 (1) ◽  
pp. 19-31 ◽  
Author(s):  
Matilde Alique ◽  
Esther Civantos ◽  
Elsa Sanchez-Lopez ◽  
Carolina Lavoz ◽  
Sandra Rayego-Mateos ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Therapeutic Target ◽  
Clinical Treatment ◽  
Renal Diseases ◽  
Potential Therapeutic Target ◽  
Renal Inflammation ◽  
Integrin Linked Kinase

There is no effective clinical treatment for chronic kidney disease. We describe in the present paper that ILK (integrin-linked kinase) is a critical regulator of AngII (angiotensin II)-mediated renal inflammation, suggesting that ILK could be a potential therapeutic target for inflammatory renal diseases.

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