Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glomerular influx of monocytes/macrophages (M/M) occurs in many immune- and non-immune-mediated renal diseases. The mechanisms targeting M/M into the glomerulus are incompletely understood, but may involve stimulated expression of chemokines. We investigated whether angiotensin II (ANG II) induces the chemokine RANTES in cultured glomerular endothelial cells of the rat and in vivo. ANG II stimulated mRNA and protein expression of RANTES in cultured glomerular endothelial cells. The ANG II-induced RANTES protein was chemotactic for human monocytes. Surprisingly, the ANG II-stimulated RANTES expression was transduced by AT2 receptors because the AT2 receptor antagonists PD 123177 and CGP-42112A, but not an AT1 receptor blocker, abolished the induced RANTES synthesis. Intraperitoneal infusion of ANG II (500 ng/h) into naive rats for 4 d significantly stimulated glomerular RANTES mRNA and protein expression compared with solvent-infused controls. Immunohistochemistry revealed induction of RANTES protein mainly in glomerular endothelial cells and small capillaries. Moreover, ANG II- infused animals exhibited an increase in glomerular ED-1- positive cells compared with controls. Oral treatment with PD 123177 (50 mg/liter drinking water) attenuated the glomerular M/M influx without normalizing the slightly elevated systolic blood pressure caused by ANG II infusion, suggesting that the effects on blood pressure and RANTES induction can be separated. We conclude that the vasoactive peptide ANG II may play an important role in glomerular chemotaxis of M/M through local induction of the chemokine RANTES. The observation that the ANG II- mediated induction of RANTES is transduced by AT2 receptors may influence the decision as to which substances might be used for the therapeutic interference with the activity of the renin-angiotensin system.
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PMID:Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. 927 21

Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-beta and deposition of extracellular matrix proteins follows, which is accompanied by fibrinoid vasculitis in small vessels of the heart and kidneys. Angiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowered blood pressure and shifted pressure natriuresis partially leftward by different mechanisms. When combined, they normalized blood pressure, pressure natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy completely. Endothelin receptor blockade had no influence on blood pressure but protected from vasculopathy and improved survival. We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFkappaB is upregulated in this model. We speculate that the transcription factors NFkappaB and AP-1 are involved with initiating chemokine and cytokine expression, leading to the above cascade. The unique model and our pharmacological probes will enable us to test these hypotheses.
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PMID:Hypertension-induced end-organ damage : A new transgenic approach to an old problem. 993 Nov 7

FcR provides a critical link between ligands and effector cells in immune complex diseases. Emerging evidence reveals that angiotensin (Ang)II exerts a wide variety of cellular effects and contributes to the pathogenesis of inflammatory diseases. In anti-glomerular basement membrane Ab-induced glomerulonephritis (GN), we have previously noted that FcR-deficient mice (gamma(-/-)) surviving from lethal initial damage still developed mesangial proliferative GN, which was drastically prevented by an AngII type 1 receptor (AT1) blocker. We further examined the mechanisms by which renin-Ang system (RAS) participates in this immune disease. Using bone marrow chimeras between gamma(-/-) and AT1(-/-) mice, we found that glomerular injury in gamma(-/-) mice was associated with CD4(+) T cell infiltration depending on renal AT1-stimulation. Based on findings in cutaneous delayed-type hypersensitivity, we showed that AngII-activated renal resident cells are responsible for the recruitment of effector T cells. We next examined the chemotactic activity of AngII-stimulated mesangial cells, as potential mechanisms coupling RAS and cellular immunity. Chemotactic activity for T cells and Th1-associated chemokine (IFN-gamma-inducible protein-10 and macrophage-inflammatory protein 1alpha) expression was markedly reduced in mesangial cells from AT1(-/-) mice. Moreover, this activity was mainly through calcineurin-dependent NF-AT. Although IFN-gamma-inducible protein-10 was NF-kappaB-dependent, macrophage-inflammatory protein 1alpha was dominantly regulated by NF-AT. Furthermore, AT1-dependent NF-AT activation was observed in injured glomeruli by Southwestern histochemistry. In conclusion, our data indicate that local RAS activation, partly via the local NF-AT pathway, enhances the susceptibility to T cell-mediated injury in anti-glomerular basement membrane Ab-induced GN. This novel mechanism affords a rationale for the use of drugs interfering with RAS in immune renal diseases.
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PMID:Susceptibility to T cell-mediated injury in immune complex disease is linked to local activation of renin-angiotensin system: the role of NF-AT pathway. 1237 Mar 42

Genetic responses that characterize experimental autoimmune myocarditis (EAM) have not yet been determined. To investigate gene expression in the myocardium of EAM, absolute copy numbers of 44 mRNA species [calcium-handling proteins, contractile proteins, natriuretic peptides (NPs), cytokines, chemokines, growth factors, renin-angiotensin-aldosterone (RAA) system, endothelins (ETs) and extracellular matrix] in synthesized cDNA from a fixed quantity of total heart RNA were assessed using real-time reverse-transcriptase PCR at days 0, 14, 21 and 28 after immunization. alpha-Cardiac myosin showed a 26.3-fold decrease and beta-cardiac myosin a 3.75-fold increase at day 14. Atrial NP and brain NP increased 47.7- and 6.35-fold at days 21 and 14 respectively. Angiotensin II type 1 receptor, angiotensin-converting enzyme and ET1 increased 22.3-fold at day 21, 6.30-fold at day 21 and 16.8-fold at day 14 respectively. Aldosterone receptor decreased 2.15-fold at day 14, but aldosterone synthetase was detected only at days 14 and 21. Interleukin (IL)-2, IL-10, interferon-gamma and monocyte chemo-attractant protein-1 increased 9.08-fold at day 14, 398-fold at day 21, 43.1-fold at day 14 and 142-fold at day 14 respectively. Collagen type 3, collagen type 1 and fibronectin increased 34.6-, 1.74- and 44.4-fold respectively at day 21. Interestingly, osteopontin showed a 4540-fold increase and it was the highest mRNA of all at day 14. An isoform of cardiac myosin and NP are dramatically changed in EAM. RAA system and ET expressions are changed differently during the EAM time course. Cytokine, chemokine and extracellular matrix greatly increase and, in particular, large numbers of osteopontin mRNA are expressed in early EAM.
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PMID:Time course of gene expression in rat experimental autoimmune myocarditis. 1244 15

We recently described that a treatment with the angiotensin AT1 receptor antagonist irbesartan inhibits atherosclerotic lesion development, macrophage accumulation, and monocyte chemoattractant protein-1 (MCP-1) as well as the chemokine KC expression in apolipoprotein E-deficient (apoE-deficient) mice. The present study addresses whether these and other chemokines are expressed not only during the initiation but also during the development of atherosclerotic lesions and whether irbesartan can inhibit the expression of these chemokines during lesion progression. The time course of lesion development was assessed in apoE-deficient mice aged 1 to 9 months and the relative expression of chemokines was quantified by RT-PCR. Significant lesion formation already appeared in 3-month-old apoE-deficient mice, and progressed further to the age of 9 months. The expression of MCP-1 and KC (the mouse homologue of Groalpha), was induced at 1 month in apoE-deficient as compared with wild type (C57/Bl6) mice, and was observed before any detectable histologic changes. MCP-1 and KC expression remained high during lesion progression. The expression of macrophage inflammatory protein-2 (MIP-2, the mouse Grobeta/gamma homologue) and macrophage inflammatory protein-1alpha (MIP-1alpha) was increased in lesions from 4-month-old mice onward, whereas Regulated upon Activation of Normal T-cells Expressed and Secreted (RANTES) was significantly induced in 6- to 9-month-old mice only. Irbesartan (50 mg/kg/d) administered from the age of 3 months onward significantly reduced the progression of the lesions as well as the expression of the chemokines. A short-term treatment with irbesartan significantly inhibited the expression of MCP-1 and KC, suggesting that activation of the renin-angiotensin system is involved in up-regulation of these chemokines and that this effect represents a potential mechanism by which irbesartan inhibits plaque development and progression.
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PMID:Lesion progression in apoE-deficient mice: implication of chemokines and effect of the AT1 angiotensin II receptor antagonist irbesartan. 1471 5

Recent experimental findings have led to renewed interest in the possible role of uric acid in the pathogenesis of both hypertension and vascular disease. Often considered an antioxidant, biochemical and in vitro data indicate that noncrystalline, soluble uric acid also can react to form radicals, increase lipid oxidation, and induce various pro-oxidant effects in vascular cells. In vitro and in vivo findings suggest that uric acid may contribute to endothelial dysfunction by inducing antiproliferative effects on endothelium and impairing nitric oxide production. Proinflammatory and proliferative effects of soluble uric acid have been described on vascular smooth muscle cells (VSMCs), and in animal models of mild hyperuricemia, hypertension develops in association with intrarenal vascular disease. Possible adverse effects of uric acid on the vasculature have been linked to increased chemokine and cytokine expression, induction of the renin-angiotensin system, and to increased vascular C-reactive protein (CRP) expression. Experimental evidence suggests a complex but potentially direct causal role for uric acid in the pathogenesis of hypertension and atherosclerosis.
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PMID:Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. 1566 Mar 33

Recent evidence indicates that the renin-angiotensin system (RAS) seems to play a considerable role in the development of tubulointerstitial (TI) lesions caused by hyperoxaluria (Hox). The purpose of the present study was to evaluate the specific mechanism by which Hox involving RAS induces chemokine and cytokine expression and, therefore, renal TI damage in the ethylene-glycol (ETG) induced hyperoxaluric rat model. Sprague-Dawley rats, separated into five groups, received: G1 regular water, and G2, G3, G4 and G5 1% ETG (a precursor for oxalates) in their drinking water for 4 weeks. An angiotensin converting enzyme inhibitor, benazepril (BZ) 10 mg/kg/day, angiotensin II receptor antagonists, subtype 1 (AT1) losartan (LOS) 40 mg/kg/day and subtype 2 (AT2) PD 123,319 (PD) 10 mg/kg/day, were administered daily to G3, G4 and G5, respectively. At the end of the study, the inflammatory response to Hox was evaluated using anti-NF-kappaB (p50), anti-IL-6, anti-MCP-1; anti-RANTES and anti-ED1 (monocytes/macrophages) in each group. In spite of the same urine oxalate levels, rats belonging to the hyperoxaluric groups treated with either BZ or LOS showed significantly (P<0.01) less TI lesions together with a lower immunoexpression of inflammatory mediators when compared with untreated hyperoxaluric animals. NF-kappaB (p50) was increased in tubular cells in the ETG group (43.6+/-8.7 positive cells/mm(2)) and was significantly (P<0.01) reduced by LOS (11.2+/-4 positive cells/mm(2)) and even more by BZ (6.1+/-2.4 positive cells/mm(2)). There was a significant (P<0.01) correlation between NF-kappaB (p50) positive cells and ED1 cells in the ETG group (r=0.88) and in the ETG+LOS group (r=0.92). LOS showed better control on IL-6 and MCP-1 with respect to untreated rats, while BZ showed the best control on RANTES and ED1 cells in comparison with untreated animals. Renal function was significantly (P<0.01) better preserved in BZ and LOS treated groups compared to both untreated animals and rats with PD, as indicated by creatinine clearance values. These results suggest that Hox stimulates the NF-kappaB cascade and, therefore, induces the overexpression of inflammatory mediators like IL-6, MCP-1, and RANTES. This pathway seems to be mediated not only by AT1 but also by AT2 receptors of angiotensin II.
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PMID:NF-kappaB and chemokine-cytokine expression in renal tubulointerstitium in experimental hyperoxaluria. Role of the renin-angiotensin system. 1628 84

Angiotensin II (AngII) mediates proinflammatory properties by activating NF-kappaB transcription factor nuclear translocation and inducing the expression of chemokines. For examination of whether AngII modulates the expression of Toll-like receptor 4 (TLR4), a key element of the innate immune system that senses LPS, mouse mesangial cells (MMC) were treated with AngII. AngII upregulated TLR4 mRNA and protein in MMC, and this effect was mediated through AngII type 1 receptors. Reporter gene experiments indicate that an activating protein-1 (AP-1) as well as an E-26 specific sequence (Ets) binding site in the TLR4 promoter are responsible for the AngII-stimulated transcriptional activity of the TLR4 gene. Preincubation of MMC with AngII enhanced LPS-induced NF-kappaB activation and chemokine expression. Immunohistochemical analyses revealed that double-transgenic rats that overexpressed human renin and angiotensinogen expressed higher levels of glomerular TLR4 compared with normal Sprague-Dawley rats. In vivo, infusion with AngII but not with norepinephrine into rats for 7 d also enhanced glomerular NF-kappaB activation after systemic application of LPS, suggesting that the effects are independent of concomitantly induced hypertension. Together, these observations suggest that AngII leads to an activation of the innate immune system by a novel mechanism involving the upregulation of TLR4. Our data contribute to a better understanding of how exogenous infections may trigger renal autoimmune processes, particularly in pathophysiologic situations with high renal AngII concentrations. Because TLR4 binds endogenous ligands (e.g., extracellular matrix components) in addition to microbial products, AngII-mediated upregulation of TLR4 also could be relevant for the development of inflammation in many noninfectious renal diseases.
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PMID:Angiotensin II upregulates toll-like receptor 4 on mesangial cells. 1667

The renin angiotensin system (RAS) participates in the pathogenesis of cardiovascular diseases. Although angiotensin II has been considered the effector peptide of RAS, accumulating evidence shows that other RAS peptides also posses important functions, some of them involved in cardiovascular pathology. Many studies support the importance of N-terminal angiotensin degradation product, angiotensin IV (AngIV), in the fields of cognition, renal metabolism, and pathophysiologic conditions. The novel data discussed here show that AngIV could contribute to cardiovascular damage. Angiotensin IV can be generated by degradation of angiotensin II, by aminopeptidase (AP) N, or by other proteases, which could be activated during tissue damage, suggesting that elevated AngIV levels can be found in pathologic conditions. Angiotensin IV binds to a specific receptor, AT(4), which has recently been identified as an insulin-regulated AP. In vascular cells, correspondence between AT(4) binding sites and insulin-regulated AP has been described. Angiotensin IV regulates cell growth in cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells (VSMCs). In VSMC, AngIV, through AT(4), independently of AT(1) and AT(2) receptors, activates the nuclear factor-kappaB pathway and up-regulates several nuclear factor-kappaB-related genes, including the monocyte chemokine monocyte chemoattractant protein-1, the adhesion molecule intercellular adhesion molecule-1, and the cytokines interleukin 6 and tumor necrosis factor alpha. These data indicate that AngIV could be involved in the vascular inflammatory response. Thus, in endothelial cells and VSMC, AngIV up-regulates plasminogen activator inhibitor-1 expression and could participate in thrombus formation. These results reveal novel concepts of RAS in the cardiovascular system, suggesting that AngIV could play an active role in vascular diseases.
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PMID:The regulation of the inflammatory response through nuclear factor-kappab pathway by angiotensin IV extends the role of the renin angiotensin system in cardiovascular diseases. 1721 Apr 74

Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-kappaB, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-kappaB activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-kappaB activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.
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PMID:Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection. 1728 30


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