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)

We present a case of a 25-year-old woman with a renin-secreting juxtaglomerular cell tumor, retroperitoneal fibrosis associated with glomerular hypertrophy, glomerulonephritis, and marked tubulointerstitial alterations. Myofibroblasts, as shown by positive immunostaining for alpha-smooth muscle actin, were found along with transforming growth factor-beta (TGF-beta) in the interstitium of the tumor-free kidney. Regarding the pathogenesis of renal fibrosis and glomerular hypertrophy, this case may provide evidence not only experimentally but also clinically that the renin-angiotensin system plays an important role because angiotensin II is known to induce renal fibrosis associated with increased TGF-beta and the appearance of myofibroblasts.
 ...
PMID:Juxtaglomerular cell tumor with retroperitoneal fibrosis and secondary immune-complex glomerulonephritis: a possible contribution of the renin angiotensin system to renal fibrosis. 1047 54

Locally increased synthesis of angiotensin II (ANG II) in the kidney has been linked to glomerular hypertrophy, glomerulosclerosis and tubulo-interstitial fibrosis observed in chronic renal failure after subtotal nephrectomy. This action of ANG II is thought to be mediated mainly by transforming growth factor-beta (TGF-beta), which stimulates the synthesis and decreases the degradation of extracellular matrix (ECM) components, including various collagen types and fibronectin. Some recent reports indicate that reduced ANG II activity diminishes TGF-beta overexpression, and in consequence renal injury. However, no studies in SNx models concerning the influence of ANG II on gene expression regulated by TGF-beta have so far been performed. Therefore, the present study has been initiated with the following aims: 1. To develop a RT-PCR assay for evaluating gene expression concerning renin (REN), angiotensinogen (ATG) and the following ECM components: transforming growth factor-beta 1 (TGF-beta 1), fibronectin (FN), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2); 2. To assess the influence of renal mass reduction (RMR) caused by subtotal (5/6) or partial (2/6) nephrectomy on gene expression for TGF-beta 1, FN, MMP-2 and TIMP-2; 3. To evaluate the correlation between expression of these genes and activity of the circulatory or renal renin-angiotensin systems; 4. To assess the influence of treatment with enalapril (angiotensin-converting enzyme inhibitor) on renal expression of these genes, renal morphology and function in rats, relative to duration of treatment and RMR. The study consisted of two independent experiments performed in adult male Sprague-Dawley rats. Ten days prior to surgery, the animals were matched for body weight and systolic blood pressure (SBP) values and subsequently were distributed into untreated (control) and enalapril treated groups. Treatment with enalapril (EN) (50 mg/l in drinking water) was started 9 days prior to surgery. The first (short-term) experiment was performed in rats with chronic renal failure caused by subtotal nephrectomy. Remnant kidneys were taken for molecular studies at the day of SNx and 3, 7 and 21 days thereafter. Blood samples collected at the time of sacrifice served to determine plasma renin activity and plasma concentration of angiotensinogen and angiotensin II. The second (long-term) experiment was done in subtotally (5/6) and partially (2/6) nephrectomized rats. Remnant kidneys were taken for molecular and morphological studies at the day of surgery and 1 or 16 weeks thereafter. 24-hour proteinuria, hematocrit, serum creatinine and creatinine clearance values were also measured. Quantitation of renal gene expression for REN, ATG, TGF-beta 1, FN, MMP-2 and TIMP-2 was performed using RT-PCR assay and comparing amounts of respective gene mRNA with house-keeping gene mRNA encoding L19 ribosomal protein. The results obtained have led to the following conclusions: 1. The RT-PCR assay developed here ensures a reliable quantitation of gene expression for renin, angiotensinogen, transforming growth factor-beta 1, fibronectin, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2. 2. Renin gene expression in the kidney depends on renal synthesis of angiotensin II. In contrast, regulation of angiotensinogen mRNA expression seems to be independent of ANG II. 3. Long-term treatment with enalapril prevents an early increase in renal TGF-beta 1 and FN gene expression, retards the progression of chronic renal failure caused by critical renal mass reduction, and prolongs survival. 4. Intrarenal activity of the renin-angiotensin system is not a principal factor in the regulation of gene transcription for matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2.
 ...
PMID:[Molecular mechanisms of nephro-protective action of enalapril in experimental chronic renal failure]. 1058 3

Previously, it was shown that 5/6 renal mass reduction by surgical excision (RK-NX) results in a marked reduction of glomerulosclerosis (GS) at 6 wk compared with the conventional 5/6 renal ablation by infarction (RK-I) model. To determine the pathogenetic correlates of the striking differences in GS, radiotelemetrically measured BP; single nephron function; glomerular volume; the temporal expression of mRNA for renin, transforming growth factor-beta, and platelet-derived growth factor-B; and plasma renin concentration were compared between RK-NX, RK-I, and sham-operated control rats. Hypertension only developed in the RK-I model, was present at 3 d after infarction, and was correlated with both an increased expression of renin mRNA by Northern analysis and elevated plasma renin concentration. Structural (glomerular volume) and functional (single nephron blood flow and GFR) indices of the compensatory adaptive response were significantly but similarly increased in the RK-NX and RK-I rats compared with sham-operated controls, indicating that these adaptations per se are not responsible for the initiation of GS after 5/6 renal mass reduction. Glomerular capillary pressure (P(GC)) was also significantly increased in both RK-I (56 +/- 2 mmHg) and RK-NX rats (50 +/- 0.9 mmHg) compared with controls (46 +/- 0.8 mmHg, P < 0.01), but the increase was significantly greater in RK-I versus RK-NX rats (P < 0.05) consistent with the higher BP in RK-I rats. These data indicate that differences in renin probably account for the early divergence of BP (and P(GC)) responses between RK-I and RK-NX models. Transforming growth factor-beta and platelet-derived growth factor-B mRNA expression in pooled RNA from kidneys from each group showed increases at 21 d along with early evidence of glomerular injury in the RK-I group but not in the RK-NX group, consistent with their postulated roles as molecular mediators of GS, but only in rats with pathologic glomerular hypertension.
 ...
PMID:Functional and structural correlates of glomerulosclerosis after renal mass reduction in the rat. 1070 73

Hypertension, a remediable risk factor for stroke, cardiovascular disease, and renal failure, affects 50 million individuals in the United States alone. African Americans (blacks) have a higher incidence and prevalence of hypertension and hypertension-associated target organ damage compared with Caucasian Americans (whites). Herein, we explored the hypotheses that transforming growth factor-beta(1) (TGF-beta(1)) is hyperexpressed in hypertensives compared with normotensives and that TGF-beta(1) overexpression is more frequent in blacks compared with whites. These hypotheses were stimulated by our recent demonstration that TGF-beta(1) is hyperexpressed in blacks with end-stage renal disease compared with white end-stage renal disease patients and by the biological attributes of TGF-beta(1), which include induction of endothelin-1 expression, stimulation of renin release, and promotion of vascular and renal disease when TGF-beta(1) is produced in excess. TGF-beta(1) profiles were determined in black and white hypertensive subjects and normotensive controls and included circulating protein concentrations, mRNA steady-state levels, and codon 10 genotype. Our investigation demonstrated that TGF-beta(1) protein levels are highest in black hypertensives, and TGF-beta(1) protein as well as TGF-beta(1) mRNA levels are higher in hypertensives compared with normotensives. The proline allele at codon 10 (Pro(10)) was more frequent in blacks compared with whites, and its presence was associated with higher levels of TGF-beta(1) mRNA and protein. Our findings support the idea that TGF-beta(1) hyperexpression is a risk factor for hypertension and hypertensive complications and provides a mechanism for the excess burden of hypertension in blacks.
 ...
PMID:Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage. 1072 60

Angiotensin peptides are potent vasoconstrictors, cell growth factors, and neuromodulators in normal and pathological situations. To assess the potential role of the angiotensins in brain tumor-associated vessels, the expression of the enzymes of the angiotensin cascade were evaluated in these tumors. The production of these bioactive peptides is dependent on the activities of exopeptidases, including several aminopeptidases and carboxypeptidases, producing angiotensin (Ang) I, II, III, IV and Ang 1-7. Human cerebral parenchymal and glioblastoma cells expressed renin, and tumor vasculature, but not glioblastoma cells, expressed angiotensin-converting enzyme. High aminopeptidase A (APA) activity, but no aminopeptidase N/B activity, was observed in human brain tumor vasculature, suggesting a predominant production of Ang III. Grafting of rat glioma cells in rat brains yielded tumors with high APA and low aminopeptidase N/B activities in tumor vessels, confirming human results. Tumor growth and APA activity in tumor vessels were not affected by chronic angiotensin-converting enzyme inhibition. The brain-derived EC219 endothelial cells expressed high APA activity, which was not involved in endothelial cell proliferation, but was down-regulated by exposure of cells to transforming growth factor-beta (TGF beta) or to TGF beta-secreting tumor cells, suggesting a role for this peptide in the control of APA activity in cerebral vasculature. Thus, APA is a potential marker of chronic dysfunction, involving loss of TGF beta function, of the metabolic blood-brain barrier, but not of neovascularization.
 ...
PMID:Regulation of aminopeptidase A in human brain tumor vasculature: evidence for a role of transforming growth factor-beta. 1087 47

Considerable evidence suggests that the intrarenal renin-angiotensin system plays an important role in diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (Ang II) receptor blockers (ARBs) can attenuate progressive glomerulosclerosis in disease models and can slow disease progression in humans. Because agents that interfere with Ang II action may decrease glomerular injury without altering glomerular pressures, it has been suggested that Ang II has direct effects on glomerular cells to induce sclerosis independent of its hemodynamic actions. To study nonhemodynamic effects of Ang II on matrix metabolism, many investigators have used cell culture systems. Glucose and Ang II have been shown to produce similar effects on renal cells in culture. For instance, incubation of mesangial cells in high-glucose media or in the presence of Ang II stimulates matrix protein synthesis and inhibits degradative enzyme (e.g., collagenase, plasmin) activity. Glucose and Ang II also can inhibit proximal tubule proteinases. Glucose increases expression of the angiotensinogen gene in proximal tubule cells and Ang II production in primary mesangial cell culture, which indicates that high glucose itself can activate the renin-angiotensin system. The effects of glucose and Ang II on mesangial matrix metabolism may be mediated by transforming growth factor-beta (TGF-beta). Exposure of mesangial cells to glucose or Ang II increases TGF-beta expression and secretion. Their effects on matrix metabolism can be blocked by anti-TGF-beta antibody or ARBs such as losartan, which also prevents the glucose-induced increment in TGF-beta secretion. Taken together, these findings support the hypothesis that the high-glucose milieu of diabetes increases Ang II production by renal, and especially, mesangial cells, which results in stimulation of TGF-beta secretion, leading to increased synthesis and decreased degradation of matrix proteins, thus producing matrix accumulation. This may be an important mechanism linking hyperglycemia and Ang II in the pathogenesis of diabetic nephropathy.
 ...
PMID:Role of angiotensin II in diabetic nephropathy. 1099 97

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.
 ...
PMID:Blockade of the renin-angiotensin and endothelin systems on progressive renal injury. 1135 55

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin-angiotensin system. This study established a UUO model in angiotensin type 1a receptor (AT1a) deficient (mutant) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney (OBK). The relative volume of the tubulointerstitium was measured by an image analyzer; deposition of collagen types III and IV and monocyte/macrophage infiltration were histologically examined using specific antibodies. Also determined were the mRNA levels of transforming growth factor-beta by Northern blot analysis. Nuclear factor-kappaB activity was assessed by gel shift assay. UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium, together with increased deposition of collagen types III and IV and number of infiltrated monocytes/macrophages in the interstitium, relative to sham-operated mice. In comparison, these changes were significantly lower in mutant mice with UUO. The mRNA level of transforming growth factor-beta was significantly higher in the OBK of wild mice with UUO compared with sham-operated mice. In contrast, the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice. Finally, UUO resulted in activation of nuclear factor-kappaB in wild mice but was inhibited in the OBK of mutant mice. The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO.
 ...
PMID:Renal interstitial fibrosis is reduced in angiotensin II type 1a receptor-deficient mice. 1115 21

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II-induced cardiac injury. We administered spironolactone (SPIRO; 20 mg. kg(-1). d(-1)), valsartan (VAL; 10 mg. kg(-1). d(-1)), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-beta(1), and the transcription factors AP-1 and nuclear factor (NF)-kappaB. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-beta(1) were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-kappaB were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-kappaB, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II-induced cardiac damage.
 ...
PMID:Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. 1123 Mar 74

The tissue renin-angiotensin system has recently been demonstrated to reduce fibrogenesis in various organs. However, little has been clarified regarding its role in hepatic fibrosis. The purpose of this study was to investigate the effect of angiotensin-converting enzyme inhibitors on liver fibrogenesis induced in rats by low-dose chronic carbon tetrachloride administration. We used lisinopril that is absorbed in its active form and not metabolized in the liver to avoid any influence by the administration of the chemical. Carbon tetrachloride was administered twice a week i.p. Twelve and 24 weeks after the start of treatment, expanded periportal fibrosis or portal-portal bridgings and severe fat deposition were observed in the rats treated with carbon tetrachloride alone, and these findings were significantly reduced with the simultaneous treatment with lisinopril. The hydroxyproline content of the liver was significantly lower in the lisinopril-treated group. Angiotensin II up-regulated mRNA of pro alpha (I) collagen and transforming growth factor-beta in isolated hepatic stellate cells. These results suggest that the local tissue renin-angiotensin system plays a role in rat hepatic fibrogenesis induced by chronic carbon tetrachloride administration and that hepatic fibrogenesis is significantly reduced by ACE inhibitors.
 ...
PMID:Anti-fibrogenic effect of an angiotensin converting enzyme inhibitor on chronic carbon tetrachloride-induced hepatic fibrosis in rats. 1155 35


<< Previous 1 2 3 4 5 6 7 8 Next >>