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 our study was to investigate the histopathological, immunohistochemical and ultrastructural effects of Losartan (a selective angiotensin II type-1 receptor blocker) on renal development in rats. Twelve pregnant rats were divided into control and experimental groups. In the experimental group, Losartan (10 mg/kg/day) was given via nasogastric tube, between the sixth day of implantation and time of sacrifice on embryonic days 18 and 20. All formalin-fixed, paraffin wax-embedded renal tissue sections were stained with hematoxylin and eosin or labelled for binding of primary antibodies against transforming growth factor-beta (TGF-beta 1,-2,-3) using an avidin-biotin-peroxidase method. For electron microscopic examination, samples were fixed with glutaraldehyde and osmium tetroxide and embedded in araldite. Glomerular basement membrane (GBM) thickness was measured and compared using an unpaired t-test. Angiotensin II type-1 receptor antagonism by Losartan inhibited renal growth and delayed nephron maturation. Increased immunoreactivity of TGF-beta's was observed in developing nephron precursors and interstitial cells in the experimental group. Electron microscopical examination showed that thickening of the GBM was normal in the control group but an irregular thickening was seen in the experimental group (p < 0.001). It was also seen that epithelial cells of developing tubules underwent apoptosis in the experimental group. Thus, renal development in rats seems to depend on an intact renin-angiotensin system.
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PMID:Histopathological and ultrastructural effects of Losartan on embryonic rat kidney. 1618 65

To clarify the beneficial effects of cilnidipine, an L- and N-type calcium channel blocker, which were clinically observed against diastolic dysfunction in hypertrophied hearts of hypertensive patients, we investigated the effects of cilnidipine on cardiac remodeling and enhanced gene expression in stroke-prone, spontaneously hypertensive rats in comparison with that of captopril, a well-known angiotensin-converting enzyme inhibitor, at threshold doses with little blood pressure lowering effect. The expression of type III collagen and beta/alpha-myosin heavy chain as well as transforming growth factor-beta, and basic fibroblast growth factor were suppressed by both treatments, indicating the prevention or amelioration of cardiac dysfunction. Such beneficial effects were much more intense with cilnidipine treatment than in captopril. These results indicate that Ca2+ is a key factor in the pathogenesis of cardiac remodeling in hypertension. One possible beneficial effect of cilnidipine in the prevention of cardiac dysfunction may be due to the decreased amount of growth factors such as transforming growth factor-beta and basic fibroblast growth factor via direct action for Ca2+ influx and also via inhibition of local renin-angiotensin system in the myocardium.
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PMID:Prophylactic effects of an N- and L-type Ca2+ antagonist, cilnidipine, against cardiac hypertrophy and dysfunction in stroke-prone, spontaneously hypertensive rats. 1633 80

Fibrosis plays a role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. A novel charcoal compound, AST-120, has been used for over a decade in Japan to prevent progression of CKD. It is thought that the oral administration of AST-120 blocks the intestinal absorption of tryptophan-derived indole. This prevents the hepatic conversion of indole to indoxyl sulfate (IS). IS has been shown to stimulate the production of profibrotic cytokines such as transforming growth factor-beta. AST-120 lowers IS in a dose dependent fashion and does not change the creatinine appearance rate in the urine. Enteric capsules containing Bifidobacterium longum have been shown to prevent progression of CKD in a preliminary study. These findings suggest that prospective clinical trials be undertaken to determine if these other potential methods of inhibiting fibrosis are useful in slowing progressive CKD.
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PMID:A nexus of progression of chronic kidney disease: charcoal, tryptophan and profibrotic cytokines. 1636 55

Pancreatic stellate cells (PSCs) are involved in pancreatic inflammation and fibrosis. Recent studies have shown that blocking the renin-angiotensin system (RAS) attenuates pancreatic inflammation and fibrosis. However, there are few data about the direct effects of high glucose on extracellular matrix (ECM) protein synthesis and angiotensin II (Ang II) induction in PSCs. PSCs were isolated from male Sprague-Dawley rats and cultured in medium containing 5.5 mM (LG group) or 27 mM D-glucose (HG group). Levels of Ang II and transforming growth factor-beta (TGF-beta) in culture media were measured and Ang II-positive cells were counted. We used real-time polymerase chain reaction (PCR) to detect Ang II receptor expression and Western blot analysis for the expression of ECM proteins such as connective-tissue growth factor (CTGF) and collagen type IV. Cells were also treated with an Ang II-receptor antagonist (candesartan, 10 microM) or angiotensin-converting enzyme (ACE) inhibitor (ramiprilat, 100 nM). Thymidine uptake by PSCs increased fourfold with high glucose treatment. Ang II levels and the proportion of Ang II-positive PSCs were significantly increased after 6 h under high-glucose conditions. TGF-beta concentrations also increased significantly with high glucose. After 72 h, the expression of CTGF and collagen type IV proteins in high-glucose cultures increased significantly and this increase was effectively attenuated by the candesartan or the ramiprilat. All together, high glucose induced PSCs proliferation and ECM protein synthesis, and these effects were attenuated by an Ang II-receptor antagonist. The data suggest that pancreatic inflammation and fibrosis aggravated by hyperglycemia, and Ang II play an important role in this pathogenesis.
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PMID:High glucose increases extracellular matrix production in pancreatic stellate cells by activating the renin-angiotensin system. 1640 93

Danggui buxue tang (DBT), a preparation containing Angelica sinensis (danggui) and Astragalus membranaceus (huangqi) at a ratio of 1 : 5, is used widely in China for stimulating red blood cell production and enhancing cardiovascular function. The present study was undertaken to characterize the effects of this preparation on diabetic nephropathy using streptozotocin-diabetic rats as a model. Streptozotocin-dependent alterations in renal weight/body weight ratio, urinary albumin and beta (2)-microglobulin concentrations, urinary albumin excretion rate, and creatinine clearance were ameliorated after eight weeks of treatment with either DBT or the angiotensin-converting enzyme inhibitor, benazepril. DBT, but not benazepril, partially attenuated the increases in blood glucose, triglycerides and cholesterol in STZ-diabetic rats. Additionally, the increased expression of transforming growth factor-beta (1) mRNA in the renal cortex due to streptozotocin-induced diabetes was modestly attenuated by these treatments. However, eight weeks of treatment with DBT failed to modify the concentration of angiotensin II in plasma or kidney, indicating that the ability of the preparation to retard the progression of kidney disease was not attributable to inhibition of the renin-angiotensin system. We propose that DBT alleviates renal alterations in diabetes and slows the progression of diabetic nephropathy by suppressing transforming growth factor-beta (1) mRNA expression. The preparation may therefore be useful as an adjuvant therapy for controlling diabetes and its complications.
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PMID:Suppression of transforming growth factor-beta1 gene expression by Danggui buxue tang, a traditional Chinese herbal preparation, in retarding the progress of renal damage in streptozotocin-induced diabetic rats. 1652 7

Glomerulosclerosis, interstitial fibrosis, and tubular atrophy occur with end-stage kidney failure, irrespective of the primary etiology. The transforming growth factor-beta (TGF-beta) is a key factor in these alterations either directly, by stimulating synthesis of extracellular matrix components and reducing collagenase production, or indirectly through other profibrogenic factors such as connective tissue growth factor (CTGF). TGF-beta is important for the proliferation of intrarenal fibroblasts and the epithelial-mesenchymal transition through which tubular cells become fibroblasts. Although several factors induce TGF-beta expression in the kidney, one very interesting aspect is the link between the renin-angiotensin-aldosterone (Aldo) system (RAAS) and TGF-beta. Angiotensin II (ANG II) stimulates TGF-beta expression in the kidney by various mechanisms and upregulates receptors for TGF-beta. ANG II can directly phosphorylate Smads without inducing TGF-beta. Recent data provide compelling evidence that other components of the RAAS including ANG III, renin, and Aldo also activate the TGF-beta system. As direct modulation of the TGF-beta system is not yet feasible in humans, angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT1)-receptor blockers are currently the most potential drugs to interfere with this ANG II-mediated TGF-beta expression. This review highlights some current aspects of the interaction between the RAAS and the TGF-beta axis.
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PMID:Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway. 1698 15

In acute injury, liver recovers completely without any scarring change or complication. However, large portion of liver is changed into fibrotic state by excessive production of extracellular matrix (ECM) under chronic injury. Excessive production of ECM results in hepatic fibrosis and repeated process of hepatic fibrosis progress into liver cirrhosis. Liver cirrhosis is an irreversible and terminal state of chronic liver disease and one of the major causes of death in Korea. To block the progression to liver cirrhosis, various studies in the field of virology and immunology have been proceeded. Recently, studies on the hepatic fibrogenesis have progressed with the development of molecular biology. Hepatic stellate cells (HSC) play a key role in the pathogenesis of hepatic fibrosis by producing ECM. The degree of hepatic fibrosis depends on the proliferation and activation of HSC and increased net production of collagen. Therefore, inhibition of HSC activation is one of the main ways to block the progression of hepatic fibrosis. Many kinds of factors such as oxidative stress, acetaldehyde, ascorbic acid, transforming growth factor-beta (TGF-beta) and carbon tetrachloride (CCl4) have been reported to activate HSC and stimulate collagen gene expression. Although there are no definite and effective antifibrogenic agents, possible candidates are antioxidants, interferon, retinoids such as beta-carotene, flavonoids, renin-angiotensin system inhibitors and peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists. We tried to evaluate the charateristics of HSC in order to develop agents that inhibit hepatic fibrogenesis.
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PMID:[Hepatic fibrogenesis]. 1713 17

Recent studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in liver fibrosis. An intrahepatic RAS is expressed in chronically damaged livers, and angiotensin-II (AT-II) reportedly stimulates contraction and proliferation of the activated hepatic stellate cells (Ac-HSC), and increases the transforming growth factor-beta (TGF-beta) expression through angiotensin type-I receptors (AT1-R). Some studies have demonstrated that the clinically used angiotensin-converting enzyme (ACE) inhibitor (ACE-I), and AT1-R blockers (ARB) significantly attenuated experimental liver fibrosis along with suppression of the Ac-HSC and hepatic TGF-beta expression. Angiotensin-II also stimulates the tissue inhibitor of metalloproteinases-1 (TIMP-1) in a dose- and time-dependent manner via protein kinase-C as an intracellular signaling cascade in the Ac-HSC, and these effects are completely suppressed by ARB. Combination treatment with low-dose interferon (IFN) and ACE-I exerts a stronger inhibitory effect than either single agent on its own. In humans it has been reported that ARB markedly improved the liver fibrosis score and TGF-beta expression in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Serum fibrosis markers also significantly improved by treatment with low-dose IFN and ACE-I in patients with chronic hepatitis C, refractory to IFN monotherapy. Collectively, these data suggest that the interaction between AT-II and AT1-R plays a pivotal role in liver fibrosis development. Because both ACE-I and ARB are widely used in clinical practice without serious side-effects, these drugs in combination with IFN may provide a new strategy for antifibrosis therapy.
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PMID:Blockade of renin-angiotensin system in antifibrotic therapy. 1756 77

In diabetes and hypertension, the induction of increased transforming growth factor-beta (TGF-beta) activity due to glucose and angiotensin II is a significant factor in the development of fibrosis and organ failure. We showed previously that glucose and angiotensin II induce the latent TGF-beta activator thrombospondin-1 (TSP1). Because activation of latent TGF-beta is a major means of regulating TGF-beta, we addressed the role of TSP1-mediated TGF-beta activation in the development of diabetic cardiomyopathy exacerbated by abdominal aortic coarctation in a rat model of type 1 diabetes using a peptide antagonist of TSP1-dependent TGF-beta activation. This surgical manipulation elevates initial blood pressure and angiotensin II. The hearts of these rats had increased TSP1, collagen, and TGF-beta activity, and cardiac function was diminished. A peptide antagonist of TSP1-dependent TGF-beta activation prevented progression of cardiac fibrosis and improved cardiac function by reducing TGF-beta activity. These data suggest that TSP1 is a significant mediator of fibrotic complications of diabetes associated with stimulation of the renin-angiotensin system, and further studies to assess the blockade of TSP1-dependent TGF-beta activation as a potential antifibrotic therapeutic strategy are warranted.
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PMID:A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II. 1764 Sep 65

Congenital obstructive nephropathy is the primary cause of end-stage renal disease in children. Rapid diagnosis and initiation of the treatment are vital to preserve function and/or to slow down renal injury. Obstructive uropathy effects -decline in the plasmatic renal flow and glomerular filtration rate, interstitial infiltrate of leukocytes, significant decrease of the urine concentration, loss of the capacity to concentrate urine as well as fibrosis and apoptosis- are a consequence of a variety of factors that work in complex ways and are still not fully understood. Mediators as angiotensin II, transforming growth factor-beta (TGF-beta) and nitric oxide (NO) have been implicated in congenital obstructive nephropathy. The renin-angiotensin system is regulated in different ways, affecting both renal structure and function, and that it in turn depends upon the duration of the obstruction. On the other hand, the role of nitric oxide in renal injury remains somewhat controversial due to the fact that it can exert opposite effects such as cytoprotective and prooxidant / proapoptotic efects as well as proinflammatory and anti-inflammatory effects. In addition, reactive oxidative species (ROS) might contribute to the progression of renal disease. During unilateral ureteral obstruction induced uncoordinated and aberrant growth may lead to the loss of cellular phenotype and apoptosis. Promoting inflammatory responses, the oxidizers can regulate the adherence of certain molecules and proinflammatory mediators, transcription factors and fibrogenic cytokines, that are clearly involved in the progression of renal disease. The congenital obstructive nephropathy is characterized by tubular atrophy, cellular proliferation, apoptosis and fibrosis; immature kidney is more susceptible than adult kidney to showing the above mentioned alterations. Apoptosis seems to be the principal mechanism that leads to tubular atrophy during the neonatal unilateral ureteral obstruction (UUO). Considering the significant role of the apoptosis in UUO, we believe of big interest the study of the regulatory factors of apoptosis in the renal obstruction neonatal. The complex biochemical and molecular events during the development, maintenance and progression of the renal injury in unilateral ureteral obstruction require further major studies to better understand the alterations mentioned above.
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PMID:Biochemical-molecular markers in unilateral ureteral obstruction. 1766 34


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