Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages

Okamura, Atsunori; Rakugi, Hiromi; Ohishi, Mitsuru; Yanagitani, Yoshihiro; Takiuchi, Shin; Moriguchi, Koji; Fennessy, Paul; Higaki, Jitsuo; Ogihara, Toshio

doi:10.1097/00004872-199917040-00012

Cited by 213 publications

(151 citation statements)

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“…In previous studies, losartan decreased the extent of atherosclerosis in apoE7/7 mice (Keidar et al, 1997) and cynomolgus monkeys (Strawn et al, 2000) even in the absence of exogenously administered Angiotensin II. AT1 receptors have been identi®ed on macrophages (Scheidegger et al, 1997;Keidar et al, 1999;Okamura et al, 1999), a cell type heavily implicated in the development of atherogenic lesions. The pro-atherogenic eects of Angiotensin II, mediated via AT1 receptors, may be through several mechanisms including stimulation of 15-lipoxygenase, (Scheidegger et al, 1997), increased cholesterol biosynthesis (Keidar et al, 1999) and increased oxidized LDL uptake (Hayek et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Antagonism of AT2 receptors augments Angiotensin II‐induced abdominal aortic aneurysms and atherosclerosis

Daugherty

Manning

Cassis

2001

British J Pharmacology

265

244

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; P=0.003). In contrast, the co-infusion of Angiotensin II with PD123319 resulted in a marked increase in the incidence and severity of aortic aneurysms. 3 To determine whether AT2 antagonism also promoted Angiotensin II-induced atherosclerosis, Angiotensin II was infused into young female apoE7/7 mice that had little spontaneous atherosclerosis. In these mice, co-infusion of PD123319 led to a dramatic increase in the extent of atherosclerosis. This increase was associated with no change in plasma lipid concentrations and only transient and modest increases in blood pressure during co-infusion with PD123319. 4 While antagonism of AT1 receptors totally prevented the formation of aneurysms, antagonism of AT2 receptors promoted a large increase in the severity of Angiotensin II-induced vascular pathology.

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Section: Discussionmentioning

confidence: 99%

Antagonism of AT2 receptors augments Angiotensin II‐induced abdominal aortic aneurysms and atherosclerosis

Daugherty

Manning

Cassis

2001

British J Pharmacology

265

244

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“…AT-II is a direct stimulus of MCP-1 in vascular smooth muscle and in the mesangial cells of the kidney (24). AT-II itself has monocyte chemoattractant activity, and activated macrophages themselves-besides being potent sources of MCP-1-can generate AT-II via an intrinsic ACE pathway (25,26). Moreover, the infusion of AT-II into rats leads to an influx of macrophages into the kidney, which can be attenuated by the administration of an AT1a-receptor antagonist (27).…”

Section: Treatment Effectsmentioning

confidence: 99%

ACE Inhibitors Improve Diabetic Nephropathy Through Suppression of Renal MCP-1

2003

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OBJECTIVE -Chemokines play an important role in the pathogenesis of diabetic nephropathy. Angiotensin II induces several fibrogenic chemokines, namely monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-␤. The progression of diabetic nephropathy can be retarded by ACE inhibitors (ACEIs) in patients with type 1 and type 2 diabetes. We examined if blockade of the renin-angiotensin system lowered urinary levels of the chemokine MCP-1 and correlated urinary MCP-1 (uMCP-1) with parameters of renal function and glucose and lipid metabolism before and after 1 year of treatment with an ACE inhibitor.RESEARCH DESIGN AND METHODS -In 22 patients with type 2 diabetes and diabetic nephropathy in stages 3-5, treatment with the ACEI lisinopril was initiated. Before treatment and after 12 months of continuous therapy, proteinuria, creatinine clearance, uMCP-1 levels, BMI, HbA 1c , and serum cholesterol were assessed. CONCLUSIONS -Blockade of the renin-angiotensin system in type 2 diabetic patients with diabetic nephropathy reduces uMCP-1 levels and improves renal function. Because MCP-1 induces monocyte immigration and differentiation to macrophages, which augment extracellular matrix production and tubulointerstitial fibrosis, pharmacological reduction of angiotensin II may also exert its beneficial effects in diabetic nephropathy by downregulation of renal MCP-1. RESULTS Diabetes Care 26:2421-2425, 2003D iabetic nephropathy due to type 2 diabetes is becoming the single most important reason for endstage renal disease in the western world (1). Besides glomerular damage and glomerulosclerosis, diabetic nephropathy is characterized by aseptic tubulitis and tubulointerstitial fibrosis (2). Macrophages and macrophage products play an important pathogenic role in tubulointerstitial inflammatory and noninflammatory conditions and have been implicated as effector cells of tubulointerstitial damage in diabetic nephropathy (3,4). Increased numbers of glomerular and interstitial macrophages have been observed in rat models of experimental diabetes and in biopsies of patients with diabetic nephropathy (5). Monocytes are attracted to the place of organ damage by monocytespecific chemokines. Monocytes follow an endothelial-bound gradient of chemokine molecules and transmigrate from the vascular bed into the tissue at the point of the highest chemokine concentration (6). Therefore, systemic levels of chemokines do not reflect their local generation. A meaningful determination of chemokine expression can only be done in the anatomical compartment where chemokines are produced or in the near vicinity thereof. In renal diseases, this is either the kidney itself or urine.Monocyte chemoattractant protein-1 (MCP-1) is the strongest known chemotactic factor for monocytes and is upregulated in many renal diseases (7), including diabetic nephropathy (8). Renal MCP-1 expression is induced by elevated glucose levels, tubular reabsorbed protein, and probably advanced glycosylated end products (9). In diabetes, the tissue reninangi...

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“…The close relation of several intracrine enzymes with monocyte differentiation and angiogenesis, coupled with recent evidence indicating the existence of pluripotent stem cells in certain monocyte populations, gives further support to investigation in this area. 38,51,70,72,73 …”

Section: The Intracrine Perspectivementioning

confidence: 99%

Intracellular Renin and the Nature of Intracrine Enzymes

Ré

2003

Hypertension

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Abstract-Recently, the binding of renin and prorenin to cellular receptors with the subsequent generation of second messengers and the production of physiological effects has been demonstrated. In addition, the internalization of prorenin by target cells has been associated with increased cellular synthesis of angiotensin and cardiac pathology. Also, a renin transcript lacking the sequences encoding a secretory signal has been reported, and this transcript appears to produce a renin that acts in the cell that synthesized it. Some years ago, we coined the term intracrine for a peptide hormone or factor that acts in the intracellular space either after internalization or retention in its cell of synthesis. Thus defined, a wide variety of peptides display intracrine functionality, including hormones, growth factors, transcription factors, and enzymes. For example, considerable evidence indicates that angiotensin II is an intracrine. Also, general principles of intracrine functionality have been developed. Thus, recent evidence demonstrates that the prorenin/renin molecule is an intracrine enzyme. Here, the actions of intracrine enzymes (angiogenin, phosphoglucose isomerase, phospholipase A2, granzyme A and B, thioredoxin, platelet-derived endothelial growth factor, and serine protease inhibitors) are reviewed. Key Words: renin Ⅲ platelet-derived growth factor Ⅲ enzymes Ⅲ angiotensin II Ⅲ phospholipases R enin gene expression leads to the synthesis of prorenin in the juxtaglomerular cells of the kidney, activation and secretion of renin by these cells, the generation of angiotensin I by renin enzymatic activity, and the subsequent generation of angiotensin II either in the plasma or tissues. However, renin, angiotensin I, and angiotensin II can also be taken up by tissues with subsequent enzymatic conversions occurring locally. Moreover, there is considerable evidence, both in animal models and in humans, in favor of the local synthesis of each of the components of the renin-angiotensin system (RAS) in various tissues leading to locally determined angiotensin generation. 1 In addition to evidence indicating local synthesis and uptake in tissues of RAS components, there is growing evidence to indicate the uptake and synthesis of components of the RAS by individual cells, thereby suggesting a new arena for the action of this physiological system. 2 Important among these new observations are studies demonstrating that (1) prorenin and renin can bind to specific cellular receptors with the generation of physiological effects, (2) prorenin, and to a lesser extent, renin, can be internalized by cells whereupon angiotensin II is produced, and (3) there exists a renin transcript in some cells that encodes a renin that is expected to be synthesized as an active, as opposed to a prorenin, and that is expected to remain in the cell because it lacks the sequence encoding the secretory signal piece (renin exon 1A). 2-13 These observations not only reveal prorenin and renin to be hormones in their own right, they suggest that pro...

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Upregulation of renin-angiotensin system during differentiation of monocytes to macrophages

Abstract: The renin-angiotensin system is markedly activated during monocyte/macrophage differentiation, and may participate in the development of atherosclerosis.

Cited by 213 publications

References 40 publications

Antagonism of AT2 receptors augments Angiotensin II‐induced abdominal aortic aneurysms and atherosclerosis

Antagonism of AT2 receptors augments Angiotensin II‐induced abdominal aortic aneurysms and atherosclerosis

ACE Inhibitors Improve Diabetic Nephropathy Through Suppression of Renal MCP-1

Intracellular Renin and the Nature of Intracrine Enzymes

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