Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology

Higuchi, Sadaharu; Ohtsu, Haruhiko; Suzuki, Hiroyuki; Shirai, Heigoro; Frank, Gerald D.; Eguchi, Satoru

doi:10.1042/cs20060342

Cited by 372 publications

(296 citation statements)

References 124 publications

(148 reference statements)

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“…These data demonstrate that AngII can increase nuclear PPAR␦:Bcl-6 binding, limiting the amount of free Bcl-6 to repress the expression of inflammatory genes normally suppressed by Bcl-6. Valsartan pretreatment greatly attenuated PPAR␦:Bcl-6 binding, indicating that this effect of AngII is mediated by the angiotensin type 1 (AT-1) receptor, which mediates most of the proinflammatory actions of AngII (27). Consistent with the change in free Bcl-6, AngIIstimulated MCP-1 expression, which is known to be regulated by Bcl-6 (28), was attenuated by GW0742 (Fig.…”

Section: Ppar␦ Activation Attenuates Angii Suppression Of the Antiinfsupporting

confidence: 63%

“…Because AngII is known to activate MAP kinase intracellular signaling pathways to promote vascular inflammation and macrophage recruitment (27,29), we examined whether PPAR␦ activation alters AngII-mediated activation of MAP kinase pathways in macrophages. We found that in mouse peritoneal macrophages AngII treatment stimulated a 2-fold increase in the phosphorylation of both the p38 and ERK1/2 MAP kinases (Fig.…”

Section: Ppar␦ Ligand Inhibits Angii-induced Activation Of Map Kinasesmentioning

confidence: 99%

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PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Takata

Liu

Yin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

195

181

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Activation of the nuclear hormone receptor peroxisome proliferatoractivated receptor ␦ (PPAR␦) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPAR␦ activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPAR␦ agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPAR␦ activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPAR␦ activation to inhibit AngII signaling, which is atheroprotective.peroxisome proliferator-activated receptor ␦ ͉ vascular inflammation ͉ macrophage

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Section: Ppar␦ Activation Attenuates Angii Suppression Of the Antiinfsupporting

confidence: 63%

Section: Ppar␦ Ligand Inhibits Angii-induced Activation Of Map Kinasesmentioning

confidence: 99%

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Takata

Liu

Yin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

195

181

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“…In contrast, the selective blockade of AT1 significantly decreased the reperfusion-induced cellular calcium increase. AT1 is more abundantly expressed in the kidney endothelial cells 32 ; thus, the simultaneous blockade of these receptors may also affect PT calcium changes.…”

Section: Discussionmentioning

confidence: 99%

Visualization of Calcium Dynamics in Kidney Proximal Tubules

Szebényi

Füredi

Kolacsek

et al. 2015

Journal of the American Society of Nephrology

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Intrarenal changes in cytoplasmic calcium levels have a key role in determining pathologic and pharmacologic responses in major kidney diseases. However, cell-specific delivery of calcium-sensitive probes in vivo remains problematic. We generated a transgenic rat stably expressing the green fluorescent protein-calmodulinbased genetically encoded calcium indicator (GCaMP2) predominantly in the kidney proximal tubules. The transposon-based method used allowed the generation of homozygous transgenic rats containing one copy of the transgene per allele with a defined insertion pattern, without genetic or phenotypic alterations. We applied in vitro confocal and in vivo two-photon microscopy to examine basal calcium levels and ligand-and drug-induced alterations in these levels in proximal tubular epithelial cells. Notably, renal ischemia induced a transient increase in cellular calcium, and reperfusion resulted in a secondary calcium load, which was significantly decreased by systemic administration of specific blockers of the angiotensin receptor and the Na-Ca exchanger. The parallel examination of in vivo cellular calcium dynamics and renal circulation by fluorescent probes opens new possibilities for physiologic and pharmacologic investigations.

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“…122 Moreover, Ang-II-mediated changes in the production of MMP-2 and TIMP-2 occur through AT1Rs and a TGF␤1-dependent mechanism, and not through hemodynamic effects. 96,97 …”

Section: Ang II and Other Profibrotic Factorsmentioning

confidence: 99%

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

Rüster

Wolf

2011

Journal of the American Society of Nephrology

171

150

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Chronic kidney disease (CKD) is increasing worldwide. Although the cause of its progression is multifactorial, 1-3 activation of the renin-angiotensin-aldosterone system (RAAS) is a key effector and RAAS inhibitors are among the beststudied renoprotective agents. 4 -7 Although the RAAS is complex, with new peptides such as angiotensin 1-7 and angiotensin IV exhibiting profibrotic effects by binding to specific receptors as well as observations that aldosterone and even renin itself can stimulate fibrogenesis in the kidney, 8 -12 and angiotensin II (Ang II) blockade can stimulate renin release, 13 the review presented here focuses exclusively on Ang II as the major component of the RAAS effect on morphogenesis. There are several excellent reviews covering the other components of the RAAS and their profibrotic actions in the kidney. 8 -10,14 The classic view of Ang II as a vasoactive agent involved in local and systemic hemodynamic regulation 15 needs extension to encompass its properties as a morphogenic cytokine with an active role in renal pathology. 16,17 Ang II was first described 2 decades ago as stimulating the hypertrophy of tubular cells and the associated increase in collagen secretion. 18,19 Fibrosis is the final common pathway leading to renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. 20 -22 Ang II modulates renal cell growth and extracellular matrix (ECM) synthesis or degradation. 17,[23][24][25] For example, overexpression of renin and angiotensinogen in rat glomeruli leads to expanded ECM without inducing systemic hypertension. 26,27 The stimulatory effects of Ang II on increased collagen expression depend on various mechanisms. In addition to angiotensin-converting enzyme (ACE), which is the most well known enzyme capable of Ang II formation, other non-ACE Ang II-generating pathways are currently under study. 28 ACE inhibitors also diminish cellular infiltrates and inflammatory markers in many models of renal injury. 29 ANG II AND TGF␤The interactions between Ang II and the TGF␤ axis are multiple and complex (Figure 1). 29 -31 TGF␤ is a fibrogenic and anti-inflammatory cytokine and plays a critical role in the pathophysiology of renal injury. 32,33 Ang II stimulates transcription and synthesis of TGF␤, particularly TGF␤1, in cultured murine proximal tubular cells and also upregulates specific receptors for TGF␤, further enhancing its profibrogenic action. 34 -36 Ang II directly stimulates complex interactions in the ABSTRACTInhibitors of the renin-angiotensin-aldosterone system attenuate glomerulosclerosis and interstitial fibrosis. Although the mechanisms underlying their antifibrotic effects are complex, angiotensin II (Ang II) emerges as a major profibrogenic cytokine. Ang II modulates renal cell growth, extracellular matrix synthesis, and degradation by multiple fibrotic pathways. One of the main targets of Ang II in renal fibrosis is TGF␤. Many, but not all, of the stimulatory effects of Ang II on fibrogenesis depend on the induction...

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Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology

Cited by 372 publications

References 124 publications

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Visualization of Calcium Dynamics in Kidney Proximal Tubules

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

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