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)

One of major causes of end-stage renal disease is glomerulonephritis, the treatment of which remains difficult clinically. It has already been shown that transgenic mice that overexpress brain natriuretic peptide (BNP), with a potent vasorelaxing and natriuretic property, have ameliorated glomerular injury after subtotal nephrectomy. However, the role of natriuretic peptides in immune-mediated renal injury still remains unknown. Therefore, the effects of chronic excess of BNP on anti-glomerular basement membrane nephritis induced in BNP-transgenic mice (BNP-Tg) were investigated and the mechanisms how natriuretic peptides act on mesangial cells in vitro were explored. After induction of nephritis, severe albuminuria (approximately 21-fold above baseline), tissue damage, including mesangial expansion and cell proliferation, and functional deterioration developed in nontransgenic littermates. In contrast, BNP-Tg exhibited much milder albuminuria (approximately fourfold above baseline), observed only at the initial phase, and with markedly ameliorated histologic and functional changes. Up-regulation of transforming growth factor-beta (TGF-beta) and monocyte chemoattractant protein-1 (MCP-1), as well as increased phosphorylation of extracellular signal-regulated kinase (ERK), were also significantly inhibited in the kidney of BNP-Tg. In cultured mesangial cells, natriuretic peptides counteracted the effects of angiotensin II with regard to ERK phosphorylation and fibrotic action. Because angiotensin II has been shown to play a pivotal role in the progression of nephritis through induction of TGF-beta and MCP-1 that may be ERK-dependent, the protective effects of BNP are likely to be exerted, at least partly, by antagonizing the renin-angiotensin system locally. The present study opens a possibility of a novel therapeutic potential of natriuretic peptides for treating immune-mediated renal injury.
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PMID:Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury. 1172 34

AIM:To investigate effect of losartan, an AT1 receptor antagonist, on hepatic fibrosis induced by CCl(4); and to determine whether or not AT1 receptors are expressed on hepatic stellate cells. METHODS AND RESULTS:Fifty male Sprague-Dawley rats, weighing (180 plus minus20)g, were randomized into five groups (control group, model group, and three losartan treated groups), in which all rats were given the subcutaneous injection of 40% CCl(4)(every 3 days for 6 weeks) except for rats of control group. Rats of losartan-treated groups were treated with losartan (20 mg/kg, 10 mg/kg, 5 mg/kg, daily gavage). After 6 weeks liver tissue and serum samples of all rats were examined. Serum hyaluronic acid (HA), procollagen type III (PC III) were detected by radioimmunoassays. van Giesion collagen staining was used to evaluate the extracellular matrix of rats with liver fibrosis. The expression of AT1 receptors, transforming growth factor-beta (TGF-beta), and alpha-smooth muscle actinalpha-SMA) in liver tissue were determined by immunohistochemical techniques. Compared with model group, serum ALT and AST of losartan-treated groups were significantly reduced (italic>t = 4.20,P < 0.01 and italic>t = 4.57,P < 0.01). Serum HA and PC III also had significant differences (italic>t = 3.53,P<0.01 and t=2.20, P<0.05). The degree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors, TGF-beta, and alpha-SMA in liver tissue.CONCLUSION:AT1 receptor antagonist, losartan, could limit the progression of the hepatic fibrosis induced by CCl(4). The mechanism may be related to the decrease in the expression of AT1 receptors and TGF-beta, ameliorating the injury of hepatocytes; activation of local renin-angiotensin system might relate to hepatic fibrosis; and during progression of fibrosis, activated hepatic stellate cells might express AT1 receptors.
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PMID:Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl(4). 1181 43

Puberty accelerates microvascular complications of diabetes mellitus, including nephropathy. Animal studies confirm a different renal hypertrophic response to diabetes before and after puberty, probably due to differences in the production of transforming growth factor-beta (TGF-beta). Many of the complex physiological changes during puberty could affect potentially pathogenic mechanisms of diabetic kidney disease. Increased blood pressure, activation of the growth hormone-insulin-like growth factor I axis, and production of sex steroids could all play a role in pubertal susceptibility to diabetic renal hypertrophy and nephropathy. These factors may influence the effects of hyperglycemia and several systems that ultimately control TGF-beta production, including the renin-angiotensin system, cellular redox systems, the polyol pathway, and protein kinase C. These phenomena may also explain gender differences in kidney function and incidence of end-stage renal disease. Normal changes during puberty, when coupled with diabetes and superimposed on a genetically susceptible milieu, are capable of accelerating diabetic hypertrophy and microvascular lesions. A better understanding of these processes may lead to new treatments to prevent renal failure in diabetes mellitus.
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PMID:Diabetic kidney disease: impact of puberty. 1221 49

Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. It has been shown that the renin-angiotensin system plays a central role in the progression of interstitial fibrosis. Recent studies indicate that endothelin, a powerful vasoconstrictive peptide, may play an important role in some types of renal disease. To investigate the effects of angiotensin II on endothelin and its receptors in the kidney, mice were subjected to UUO and treated with or without enalapril, an orally active angiotensin-converting enzyme inhibitor, in their drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we measured the levels of endothelin-1, endothelin A, and endothelin B (ET(B)) along with transforming growth factor-beta, TNF-alpha, and collagen type IV mRNA expression in the kidney with UUO and the contralateral kidney along with interstitial expansion in the kidney cortex by a standard point counting method. We found that enalapril administration ameliorated the increased expression of ET-1 mRNA in the obstructed kidney by 44% (P < 0.02). Although the level of endothelin A mRNA expression was significantly increased in the obstructed kidney, it was not affected by enalapril. We found that enalapril treatment increased ET(B) mRNA expression by 115% (P < 0.05) and protein expression (measured by Western blot) in the kidney with an obstructed ureter. Enalapril treatment alone inhibited the expansion of interstitial volume due to UUO by 52%. Cotreatment with enalapril and the ET(B) receptor antagonist BQ-788 inhibited the expression of interstitial volume by only 19%. This study confirms that enalapril inhibits the interstitial fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen effect of enalapril on the obstructed kidney by potentially stimulating the production of nitric oxide through an increased expression of the ET(B) receptor.
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PMID:ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction. 1247 37

In addition to hyperglycemia, hypertension and the renin-angiotensin system have been consistently implicated in the pathogenesis of diabetic nephropathy. Each of these pathogenetic factors may induce changes in cellular function by a common intracellular signaling pathway, the activation of protein kinase C (PKC) beta. The present study thus sought to determine the in vivo effect of PKC beta inhibition in experimental diabetic nephropathy in the setting of continued hyperglycemia, hypertension, and activation of the RAS. Studies were conducted in the (mRen-2)27 rat, a rodent that is transgenic for the entire mouse renin gene (Ren-2) and develops many of the structural, functional, and molecular characteristics of human diabetic nephropathy when experimental diabetes is induced with streptozotocin (STZ). Six-week-old female Ren-2 rats received an injection of STZ or vehicle and were maintained for 6 months. Within 24 h, diabetic rats were further randomized to receive treatment with the specific PKC beta inhibitor, LY333531, admixed in diet (10 mg x kg(-1) x d(-1)) or no treatment (n = 8/group). Diabetic rats developed albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis with a concomitant increase in transforming growth factor-beta (TGF-beta). Western blot analysis demonstrated increased PKC beta in diabetic animals, localized by immunofluorescence to the glomerular mesangium. In vivo inhibition of PKC beta with LY333531 led to a reduction in albuminuria, structural injury, and TGF-beta expression, despite continued hypertension and hyperglycemia.
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PMID:Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. 1254 Jun 29

Prevalence of diabetic nephropathy is increasing. Understanding of pathogenesis and clinical picture helps to manage this disease. Recent data of the research of this disease support that the renin-angiotensin system plays a pivotal role in the pathogenesis. Hyperglycaemia activates the renin-angiotensin system and induces transforming growth factor-beta expression. These both lead to glomerulosclerosis and tubulointerstitial fibrosis. Diabetic nephropathy develops earlier and progress faster in patients with DD or ID genotypes of angiotensin-I-converting-enzyme gene. Angiotensinogen and type 1 angiotensin-II-receptor gene mutations may be also predisposing factors for diabetic nephropathy. All these factors can be responsible for the hyperfiltration, albuminuria, salt sensitivity, and hypertension, which are characteristic features of diabetic nephropathy. According to these, one can suppose that inhibitors of the renin-angiotensin system are effective in the prevention and treatment of this disease. Evidence of clinical studies suggests that angiotensin-I-converting-enzyme inhibitors in type 1 diabetes can prevent overt nephropathy, decrease proteinuria, inhibit the loss of the glomerular filtration and decelerate progression. Angiotensin-II-receptor blockers exert the same effect in type 2 diabetic patients, and presumably angiotensin-I-converting-enzyme inhibitors have similar activity in this group of patients. That is why, in the case of intolerance of one class of drugs, the other should be substituted. Combination therapy of angiotensin-I-converting-enzyme inhibitors with angiotensin-II-receptor blockers can be the choice of treatment in the future.
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PMID:[Role of the renin-angiotensin system in the pathogenesis, clinical picture and treatment of diabetic nephropathy]. 1272 86

Angiotensin II (ANG II), generated by activation of local renin-angiotensin systems, is believed to play an important role in tissue repair and remodeling, in part via transforming growth factor-beta (TGF-beta). Angiotensin-converting enzyme (ACE) inhibitors have been shown to abrogate experimental lung injury via a number of potential mechanisms; however, the potentially fibroproliferative role for ANG II in the lung has not been characterized. We hypothesized that, after lung injury, ANG II would stimulate fibroblast procollagen synthesis and promote lung collagen deposition in rats. In vitro, ANG II was a potent inducer of procollagen production in human lung fibroblasts via activation of the type 1 receptor and, at least in part, via the autocrine action of TGF-beta. After bleomycin-induced lung injury, an increase in lung ANG II concentration was observed by day 3 that preceded increases in lung collagen and was maintained until death at day 21. Administration of an ACE inhibitor (ramipril) reduced ACE activity, ANG II concentration, TGF-beta expression, and collagen deposition. Losartan (an ANG II type 1 receptor antagonist) also attenuated the increase in TGF-beta expression and lung collagen deposition. These observations suggest that ANG II, possibly generated locally within the lung, may play an important role in the fibrotic response to acute lung injury, at least in part via the action of TGF-beta. ACE inhibitors and receptor antagonists, already widely used clinically, should be assessed as potential new therapies for fibrotic lung disease.
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PMID:Angiotensin II and the fibroproliferative response to acute lung injury. 1275 87

Previous studies have showed that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of liver cirrhosis. The localization of angiotensin II receptor in hepatic stellate cells opens up a new research direction of RAS in the regulation of liver fibrosis. However, the potential role of angiotensin II on Kupffer cells remains unexplored. As Kupffer cells are actively involved in the fibrotic process, the present study aimed, specifically, to demonstrate the presence of key RAS components, with particular reference to the AT(1) receptor, and its potential role in hepatic Kupffer cells. The expression of key RAS components in rat liver and isolated hepatic Kupffer cells was analyzed by RT-PCR. The expression and precise localization of AT(1) receptors in hepatic Kupffer cells were investigated by Western blot analysis and immunofluorescent double staining, respectively. The effect of angiotensin-stimulated Kupffer cells on the expression of the fibrogenic factors, i.e. transforming growth factor-beta (TGF-beta) and fibronectin, was examined by semi-quantitative RT-PCR. RT-PCR analysis showed that mRNA of several key RAS components-angiotensin II receptors, angiotensinogen, renin and angiotensin-converting enzyme, particularly the AT(1) receptors, was expressed in the liver and isolated hepatic Kupffer cells. The AT(1) receptor protein was consistently expressed in hepatic Kupffer cells as evidenced by Western blot analysis. Double immunostaining confirmed that the AT(1) receptors were specifically localized to the Kupffer cells from the liver and isolated hepatic Kupffer cells. On the other hand, angiotensin II stimulated mRNA expression of TGF-beta and fibronectin, which could be inhibitable by saralasin and losartan, the nonselective and specific antagonists for AT(1) receptors, respectively. The present findings clearly demonstrated the expression, localization and potential role of local RAS components with particular emphasis on the AT(1) receptors in hepatic Kupffer cells. The intimate interaction of angiotensin II with its AT(1) receptor located in the Kupffer cells and its fibrogenic action may represent a regulatory mechanism in the development of liver fibrosis such as inflammation and cirrhosis.
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PMID:Expression and localization of AT1 receptors in hepatic Kupffer cells: its potential role in regulating a fibrogenic response. 1459 16

Obstructive nephropathy refers to the mechanical or functional changes in the urinary tract that interfere with normal urinary flow. Once obstruction is set, it leads to progressive renal damage that is mainly characterized with tubulointerstitial fibrosis. Here we reviewed the pathophysiology of urinary tract obstruction and indicated future therapeutic options. Following complete unilateral ureteral obstruction, there is a progressive fall in renal blood flow and glomerular filtration rate, and is a increase in intratubular pressure. These events activate the plasma and tissue renin-angiotensin systems (RAS). It has been proved that upregulated angiotensin II is one of the crucial factors those are responsible for the subsequent deleterious process. Angiotensin II induces transforming growth factor-beta, which causes overproduction of extracellular matrix (ECM) proteins like collagen, fibronectin, etc. The ECM proteins are dominantly accumulated in tubulointerstitium and result in deterioration of renal function. Along with the activation of the RAS, tissue ischemia and mononuclear leukocyte infiltration also modulate the fibrotic changes. The process from the RAS activation to renal fibrosis is observed not only in obstructive nephropathy but also in other renal diseases and is called the Final Common Pathway. Mechanical release of the obstruction is to perform in terms of the treatment, however, several promising pharmaceutical options are now under investigation.
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PMID:[Pathophysiology and clinical implication of obstructive nephropathy]. 1467 94

Acute and chronic renal diseases remain common complications of systemic sclerosis. Although treatment for acute scleroderma renal crisis may arrest the rapid progression of renal disease, many patients develop persistent renal dysfunction. Based on recent insights gained from progressive renal diseases of diverse etiologies, novel approaches to understanding the pathobiology of scleroderma renal disease may be applicable. Key factors involved in progression of renal disease include accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments, epithelial to mesenchymal transformation, and vascular changes. The relevant factors mediating these events include the renin-angiotensin system, the profibrotic growth factors, transforming growth factor-beta and connective tissue growth factor, and reactive oxygen species. Much of the molecular details of the role of these factors have been revealed and promise to alter the practice of therapy of progressive renal disease.
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PMID:The pathogenesis of fibrosis and renal disease in scleroderma: recent insights from glomerulosclerosis. 1501 45


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