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

The aim of the present study was to test the hypothesis that elevation of prorenin in plasma is sufficient to induce cardiac fibrosis. Normotensive cyp1a1ren-2 transgenic rats with normal plasma prorenin and aldosterone levels were given 0.125% indole-3-carbinol (I3C) orally for a period of 12 wk. Plasma prorenin and aldosterone levels were determined in 4-wk intervals, and cardiac marker enzymes for hypertrophy, fibrosis, and oxidative stress as well as cardiac pathology were investigated. In I3C-treated cyp1a1 ren-2 transgenic rats, plasma prorenin concentrations were >100-fold elevated (> or = 7.1 + or - 2.6 microg ANG I.ml(-1).h(-1) vs. < or = 0.07 + or - 0.1; P < 0.001), whereas active renin levels were suppressed (0.09 + or - 0.02 vs. 0.2 + or - 0.1; P < 0.05). Aldosterone concentrations were elevated three- to fourfold for a period of >4 wk (574 + or - 51 vs. 160 + or - 68 pg/ml; P < 0.01). After 12 wk of I3C, rats exhibited moderate cardiac hypertrophy (heart weight/body weight 2.5 + or - 0.04 vs. 3.1 + or - 0.1 mg/g; P < 0.01). There was a slight increase in mRNA contents of endothelin 1 (1.21 + or - 0.08 vs. 0.75 + or - 0.007; P < 0.001), NADP oxidase-2 (1.03 + or - 0.006 vs. 0.76 + or - 0.04; P < 0.001), transforming growth factor-beta (0.99 + or - 0.06 vs. 0.84 + or - 0.04; P < 0.05), collagen type I (1.32 + or - 0.32 vs. 0.94 + or - 0.18; P < 0.05), and intercellular adhesion molecule-1 (1.12 + or - 0.12 vs. 0.84 + or - 0.08; P < 0.05). These genes are known to be stimulated by the renin-angiotensin system. There were no histological signs of fibrosis in the heart. We found that prorenin and aldosterone alone are not sufficient to induce considerable cardiac fibrosis in the absence of sodium load.
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PMID:Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism. 1974 60

We recently showed that losartan and paricalcitol are synergistic in the treatment of diabetic nephropathy in a model of type 1 diabetes. To test this strategy in a model of type 2 diabetes, we treated 2-month-old diabetic Lprdb/db mice with losartan, paricalcitol, or a combination of losartan and paricalcitol for 3 months. Vehicle-treated diabetic mice developed progressive albuminuria and glomerular abnormalities with mesangial expansion and glomerulosclerosis compared to their non-diabetic littermate control mice. Accompanying damage of the glomerular filtration barrier was a marked reduction in podocyte number as well as reduced expression of slit diaphragm proteins. Further, there was increased glomerular expression of extracellular matrix proteins, monocyte chemoattractant protein-1 and transforming growth factor-beta. Losartan or paricalcitol each alone moderately ameliorated albuminuria and glomerular damage. However, their combined use showed a dramatic therapeutic synergism, manifested by prevention of progressive albuminuria, restoration of the glomerular filtration barrier, reversal of the decline in slit diaphragm proteins, reduced synthesis of extracellular matrix proteins, and reduction of glomerulosclerosis. These effects were accompanied by blockade of the compensatory increase of renin production and angiotensin I/II accumulation in the kidney. Thus, our study further shows that vitamin D analogs can increase the efficacy of AT1 receptor blockade, leading to a more effective prevention of kidney disease in type 2 diabetes.
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PMID:Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes. 2046 30

There is accumulating evidence that proteinuria is not merely a biomarker for the progression of chronic kidney disease (CKD), but also a mediator of this devastating disorder. Indeed, albumin, one of the major components found in proteinuria, causes proinflammatory and profibrotic changes in cultured proximal tubular cells. Further, numerous studies have demonstrated the active participation of the renin-angiotensin system (RAS) in the pathogenesis of CKD as well. However, the role of the RAS in albumin-elicited tubular cell damage remains to be elucidated. Therefore, in this study, we studied whether and how irbesartan, an angiotensin II type 1 receptor blocker, could inhibit albumin-elicited proximal tubular cell apoptosis and injury in vitro. Bovine serum albumin (BSA) increased oxidative stress generation in human cultured proximal tubular cells, which was blocked by the treatment with irbesartan. Irbesartan was also found to block the BSA-induced apoptotic cell death as well as up-regulation of plasminogen activator inhibitor-1 and transforming growth factor-beta mRNA levels in tubular cells. The present study suggests that there could exist a pathophysiological crosstalk between the RAS and albumin overload in proximal tubular cell apoptosis and damage. Blockade of the RAS by irbesartan may play a protective role against tubular cell injury by attenuating the deleterious effects of albumin.
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PMID:Irbesartan inhibits albumin-elicited proximal tubular cell apoptosis and injury in vitro. 2021 30

Morphological changes of the peritoneal membrane that occur over time among patients on peritoneal dialysis include fibrosis and neoangiogenesis. While the pathophysiologic mechanisms underlying these changes are not fully understood, the activation of the renin-angiotensin-aldosterone system (RAAS) may have an important role. Components of the RAAS are constitutively expressed within peritoneal mesothelial cells, and are upregulated in the presence of acute inflammation and chronic exposure to peritoneal dialysate. The high glucose concentration, low pH, and the presence of glucose degradation products in peritoneal dialysis solutions have all been implicated in modulation of peritoneal RAAS. Furthermore, activation of the RAAS, as well as the downstream production of transforming growth factor-beta, contributes to epithelial-to-mesenchymal transformation of mesothelial cells, resulting in progressive fibrosis of the peritoneal membrane. This process also leads to increased vascular endothelial growth factor production, which promotes peritoneal neoangiogenesis. Functionally, these changes translate into reduced ultrafiltration capacity of the peritoneal membrane, which is an important cause of technique failure among patients on long-term peritoneal dialysis. This brief review will describe our current state of knowledge about the role of peritoneal RAAS in peritoneal membrane damage and potential strategies to protect the membrane.
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PMID:The renin-angiotensin-aldosterone system in peritoneal dialysis: is what is good for the kidney also good for the peritoneum? 2115 62

Arterial aging is a predominant risk factor for the onset of cardiovascular diseases, such as hypertension, myocardial infarction, or stroke. Aging is associated with intravascular renin-angiotensin system activation, increased vascular stiffness, intima-media thickening, and a proinflammatory phenotype. Little is known about the influence of aldosterone on arterial aging. Hence, we hypothesized that aldosterone and mineralocorticoid receptor (MR) activation might contribute to and possibly accelerate the arterial aging process. We demonstrate increased MR expression in whole aortae and early passage aortic vascular smooth muscle cells from aged (30 months) compared with adult (8 months) F344XBN rats. Sensitivity to aldosterone-induced extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activity is increased in aged cells. MR blockade and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase inhibition prevent age-associated increases of transforming growth factor-beta, intercellular adhesion molecule 1, and procollagen 1. Aldosterone increases expression of proinflammatory marker proteins, shifting the phenotype of adult vascular smooth muscle cells toward the proinflammatory phenotype of aged rats. Epidermal growth factor receptor expression is increased with age and by aldosterone, and inhibition of epidermal growth factor receptor tyrosine kinase decreases age-associated proinflammatory marker expression. Our data support the hypothesis that increased constitutive MR signaling may promote and amplify age-associated inflammation that accompanies arterial aging through increased angiotensin II-stimulated expression of MR and enhanced sensitivity to aldosterone-mediated extracellular signal-regulated kinase 1/2 activation, likely related to increased epidermal growth factor receptor expression.
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PMID:Elevated mineralocorticoid receptor activity in aged rat vascular smooth muscle cells promotes a proinflammatory phenotype via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and epidermal growth factor receptor-dependent pathways. 2042 14

Acute kidney injury (AKI) in critically ill patients is a devastating illness associated with prolonged hospital stay and high mortality. Limited progress has been made in the field of AKI, and its treatment using renal replacement therapy, at best, only provides partial renal support. Ischemia-reperfusion rodent AKI models do not resemble human renal injury and the absence of renal biopsy data limits our understanding of the pathophysiology of human AKI. However, laboratory and clinical evidence suggests that the inflammatory milieu leads to dysfunction of renal cells and this may be the key factor leading to AKI. Cells in injured tissues release immunological danger signals or danger-associated molecular pattern molecules which communicate with remote organs including the kidney, where they activate dendritic cells and T cells and thus initiate inflammation. Once the initial insult has passed, tubular epithelial cells undergo dedifferentiation, reacquire progenitorial ability to proliferate, migrate, and redifferentiate into mature intrinsic cells. Dissonance of mediator secretion and cell responses may lead to persistent injury and de novo chronic kidney disease. A number of soluble mediators including transforming growth factor-beta (TGF-beta) initiate a variety of pathophysiological processes at the beginning of kidney injury. TGF-beta also plays a fundamental role in cell proliferation and interstitial fibrosis in later phases. The renin-angiotensin-aldosterone system, especially angiotensin II, contributes to kidney injury through the angiotensin II type 1 receptor, TGF-beta receptor Smad and epidermal growth factor receptor by affecting general angiostasis and vascular remodeling, indirectly modulating inflammation and cell reactions. We review the pathophysiology of AKI in light of new information regarding renal injury and repair.
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PMID:Pathophysiology of acute kidney injury: a new perspective. 2042 54

Angiotensin II influences development of left ventricular hypertrophy (LVH) by stimulating cardiomyocyte hypertrophy, fibroblast proliferation, and collagen synthesis. Because pro-fibrotic actions of angiotensin may be mediated by increased production of transforming growth factor-beta(1) (TGF-beta(1)), we assessed whether serum TGF-beta(1) levels might reflect involvement in LVH development. We analyzed relationships between left ventricular mass and levels of renin, aldosterone, and TGF-beta(1) in 67 hypertensive subjects (mean age 64 +/- 11.3 years) with electrocardiographic evidence of LVH. Levels were obtained after a 2-week washout of antihypertensive medications; two-dimensional echocardiography was subsequently performed. Linear regression analysis showed a correlation between TGF-beta(1) and LV mass (r = 0.36, P = .002). This was apparently explained by the correlation between TGF-beta(1) and left ventricular diastolic internal diameter (r = 0.42, P < .001), because no correlation between TGF-beta(1) levels and LV wall thickness was found. In multivariate analysis, the correlation between TGF-beta(1) and internal diameter remained significant (r = 0.39, P = .0014). There were no racial differences in levels of TGF-beta(1) or left ventricular geometry, and no correlations between age, blood pressure, renin, aldosterone, and left ventricular mass or dimensions. These findings indicate that serum TGF-beta(1) levels are related to left ventricular structure in hypertensive subjects, suggesting its possible involvement in the process of hypertensive left ventricular remodeling.
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PMID:Association between transforming growth factor-beta(1) and left ventricular mass and diameter in hypertensive patients. 2047 Sep 98

In recent years the actions of intracellular-acting, extracellular signaling proteins/peptides (intracrines) have become increasingly defined. General principles of intracrine action have been proposed. Mitochondria represent one locus of intracrine action, and thus far, angiotensin II, transforming growth factor-beta, growth hormone, atrial natriuretic peptide, Wnt 13, stanniocalcin, other renin-angiotensin system components, and vascular endothelial-derived growth factor, among others, have been shown to be mitochondria-localizing intracrines. The implications of this mitochondrial intracrine biology are discussed.
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PMID:The mitochondrial component of intracrine action. 2062 10

A vast majority of gene polymorphism studies in renal transplantation focus on short-term outcomes such as acute rejection. The main purpose of this article is to review the literature available and studies that have examined the association between the gene polymorphisms and long-term renal allograft functions. In this review, we focus on commonly reported genes in the renin angiotensin system, transforming growth factor-beta gene, and metalloproteinases on the incidence and progression of chronic renal allograft dysfunction.
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PMID:Gene polymorphisms in renal transplantation. 2080 14

CKD is a major public health problem in the developed and the developing world. The degree of proteinuria associated with renal failure is a generally well accepted marker of disease severity. Agents with direct antiproteinuric effects are highly desirable therapeutic strategies for slowing, or even halting, progressive loss of kidney function. We review progress on therapies acting further downstream of the renin-angiotensin-aldosterone system pathway (e.g., transforming growth factor-beta antagonism, endothelin antagonism) and on those acting independent of the renin-angiotensin-aldosterone system pathway. In all, we discuss 26 therapeutic targets or compounds and 2 lifestyle changes (dietary modification and weight loss) that have been used clinically for diabetic or nondiabetic kidney disease. These therapies include endogenous molecules (estrogens, isotretinoin), biologic antagonists (monoclonal antibodies, soluble receptors), and small molecules. Where mechanistic data are available, these therapies have been shown to exert favorable effects on glomerular cell phenotype. In some cases, recent work has indicated surprising new molecular pathways for some therapies, such as direct effects on the podocyte by glucocorticoids, rituximab, and erythropoietin. It is hoped that recent advances in the basic science of kidney injury will prompt development of more effective pharmaceutical and biologic therapies for proteinuria.
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PMID:Off the beaten renin-angiotensin-aldosterone system pathway: new perspectives on antiproteinuric therapy. 2178 36


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