Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis and deposition of collagen and other proteins has been measured in the aorta of the rat by radiolabeling in short term organ culture. Under these conditions, the synthesis of collagen and other proteins is linear for at least five hours. Autoradiography demonstrates a labeling in all cell layers and protein deposition in the extracellular matrix. Hypertension was induced by renal ischemia using Goldblatt's technique. The synthesis and deposition of collagen was stimulated in aorta from the first week of hypertension and in pregnancy, and was even more increased in hypertensive pregnant animals. Reserpine suppresses the rise in blood pressure in operated animals and prevents these modifications.
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PMID:Aortic collagen biosynthesis during renal hypertension, pregnancy and hypertension during pregnancy in the rat. 36 58

The major risk factor associated with the appearance of adverse cardiovascular events and outcome attributable to cardiovascular disease is left ventricular hypertrophy (LVH). Why this should be so resides not in the increase in myocardial mass per se, but in the disruption of myocardial structure. An abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighboring interstitial spaces represents such a distortion in structure. Furthermore, this fibrosis disrupts the electrical and mechanical behavior of the hypertrophied myocardium. Mechanisms responsible for fibrillar collagen accumulation have been examined in intact animals and cultured cardiac fibroblasts. In vivo studies indicate that myocardial fibrosis is associated with the presence of chronic mineralocorticoid excess, relative to sodium intake and excretion, not hemodynamic workload. Accordingly, fibrosis can appear in both the hypertensive, hypertrophied and nonhypertensive, nonhypertrophied ventricles. In both primary and secondary hyperaldosteronism it was possible to prevent myocardial fibrosis with an aldosterone receptor antagonist, while in unilateral renal ischemia angiotensin converting enzyme (ACE) inhibition was similarly cardioprotective. A regression in fibrous tissue and normalization of diastolic stiffness has also been possible using ACE inhibition, bringing forward the concept of cardioreparation and the notion that heart failure due to fibrosis may be reversible. In vitro studies indicate that effector hormones of the renin-angiotensin-aldosterone system stimulate fibroblast collagen synthesis. Aldosterone, in pathophysiologic concentrations, and angiotensin II, in much larger concentrations, each enhance collagen synthesis without altering the mitogenic potential of these cells. Thus, elevations in circulating aldosterone and angiotensin II, relative to sodium intake, have the potential to not only alter sodium homeostasis and vascular tonicity, but also the structure of cardiovascular tissue. Thus, myocardial fibrosis represents a structural basis for pathologic hypertrophy and ultimately accounts for the appearance of adverse cardiovascular events and outcomes.
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PMID:Pathologic hypertrophy with fibrosis: the structural basis for myocardial failure. 136 63

An abnormal elevation in collagen concentration or myocardial fibrosis occurs in the hypertrophied left ventricle of the rat with renovascular hypertension (RHT). The structural nature and functional consequences of this fibrosis and the mechanisms involved in its appearance were reviewed for various phases of hypertrophy. Within days after the onset of renal ischemia, type I collagen messenger ribonucleic acid is expressed. An interstitial fibrosis follows, characterized by an increased dimension of existing perimysial fibers and the appearance of fibrillar collagen in spaces previously devoid of collagen, together with a perivascular fibrosis of intramyocardial coronary arteries. These expressions of myocardial fibrosis are associated with an increase in diastolic and systolic myocardial stiffness. Endomyocardial fibrosis serves to further increase diastolic stiffness while myocytes encircled by fibrillar collagen become atrophic. Each of these consequences of myocardial fibrosis reduce myocyte length-dependent force generation. At 32 weeks of RHT there is an obvious diastolic and systolic dysfunction of the ventricle together with heart failure that includes ventricular dilatation, wall thinning and reduced ejection fraction. The mechanisms involved in mediating fibrosis in RHT appear to be multiple. Myocyte necrosis and fibroblast proliferation have been associated with elevated circulating angiotensin II. Necrosis in RHT was not seen with captopril pretreatment or in the hypertension and hypertrophy that accompanied infrarenal aorta banding. An alteration in coronary artery permeability may be responsible for the perivascular fibrosis that is not seen with captopril pretreatment. Thus in RHT, the hemodynamic status of the ventricle determines myocyte hypertrophy while the elevation in circulating angiotensin II is responsible for the remodeling of nonmyocyte compartments, including the appearance of myocardial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. 213 51

Left ventricular hypertrophy is based on cardiac myocyte growth. The hypertrophic process can be considered heterogeneous based on whether it also includes a remodeling and accumulation of fibrillar types I and III collagens that are responsible for impaired myocardial stiffness. In the heart, the messenger RNA (mRNA) for fibrillar collagen types I and III has been detected only in cardiac fibroblasts, whereas mRNA for basement membrane collagen type IV is present in both fibroblasts and myocytes. We studied the early and long-term expression of these collagenous proteins in rat myocardium after abdominal aortic banding with renal ischemia. Complementary DNA probes for rat pro-alpha 2 (I), mouse type III and mouse type IV collagens, and chicken beta-actin were used. Northern and dot blot analysis on total RNA extracted from left ventricular tissue indicated a sixfold increase in steady-state levels of mRNA for collagen type I on day 3 of abdominal aortic banding, which had declined to control levels by day 7 where it remained rather constant at 4 and 8 weeks. Type III collagen showed a similar pattern of gene expression after banding. mRNA levels for type IV collagen, on the other hand, were elevated on day 1 after banding, returning to control at day 7 and remaining constant. Actin mRNA levels also increased on day 1 of banding, followed by a rapid return to control levels. Monospecific antibody to types I and III collagens and immunofluorescent light microscopy on frozen sections of the myocardium revealed that at 1 week after banding, the distribution and density of these collagens were similar to those of control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in pressure overloaded rat myocardium. 214 89

In arterial hypertension associated with primary or secondary hyperaldosteronism myocardial fibrosis is an important determinant of pathologic hypertrophy. To further examine the relationship between elevations in plasma aldosterone (ALDO) and myocardial fibrosis, we analysed perivascular collagen area (PVCA) and interstitial collagen volume fraction (CVF) by videodensitometry and hydroxyproline concentration (HPro) by high-performance liquid chromatography. We examined both the left (LV) and right (RV) ventricles in the following rats models of primary or secondary hyperaldosteronism of eight weeks duration: unilateral renal ischemia (RHT); continuous ALDO administration via osmotic minipumps (0.75 microgram/h s.c.) and enhanced dietary sodium following uninephrectomy (AL); in RHT and AL after pre- and continuous treatment with either 20 (S) or 200 (SS) mg/kg/day s.c. of the aldosterone receptor antagonist, spironolactone; in AL after pre- and continuous treatment with 50 mg/kg/day oral captopril (AL + CAP); as well as in age and sex matched controls (C). Systolic arterial pressure was comparably elevated in RHT and AL (202 +/- 12 and 193 +/- 7 mmHg, respectively; P < 0.0005 vs C); it remained elevated with low dose spironolactone in either model of arterial hypertension, but was normalized with high dose spironolactone or captopril in AL. Left ventricular hypertrophy (LVH), expressed as significantly elevated LV/RV weight or LV/BW ratios, was present in all experimental groups, excluding AL + SS and AL + CAP, when compared with C (P < 0.005). In each ventricle, CVF and PVCA were increased (P < 0.005) in either model of hypertension and in AL + CAP, but were no different from C in all groups receiving either dose of spironolactone. Similar findings were observed for HPro. Thus, myocardial fibrosis was comparable in primary or secondary hyperaldosteronism, wherein elevations in plasma aldosterone, relative to increased sodium intake, are associated with arterial hypertension. The competitive ALDO receptor antagonist, spironolactone, was able to prevent fibrosis in either model irrespective of the development of LVH and the presence of hypertension. Captopril prevented hypertension and LVH, but not unexpectedly it did not prevent myocardial fibrosis in primary hyperaldosteronism. These findings provide further evidence that in these rat models increased plasma ALDO, relative to dietary sodium, plays a major role in the adverse accumulation of collagen that appears in the myocardium.
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PMID:Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. 837 16

Chronic activation of the circulating renin-angiotensin-aldosterone system (RAAS), as can occur with unilateral renal ischemia (URI), is associated with an adverse structural remodeling of the right and left ventricles characterized by reparative (i.e., microscopic scars) and reactive (i.e., perivascular/interstitial) fibrosis. The time course and cells involved in fibroplastic and fibrogenic phases of these events are unclear. Hearts were examined over the course of 8 weeks in rats infused with either angiotensin II or aldosterone, and compared to rats with URI. Tissue sections from the same heart were stained with hematoxylin and eosin, collagen specific picrosirius red, or immunolabeled with PCNA or alpha smooth muscle actin antibody. With angiotensin II or renal ischemia, fibroblast proliferation, presenting as focal accumulations at both sites of myocyte necrosis and widespread perivascular locations, was present in each ventricle on days 2 and 4, but not thereafter, alpha-Smooth muscle actin containing cells (myofibroblasts) appeared at day 2 and persisted through week 2 with renal ischemia and week 6 with angiotensin II. Macrophages, neutrophils and lymphocytes were transiently found at sites of necrosis between day 2-4 of renal ischemia. AngII-induced necrotic sites were characterized by macrophages and lymphocytes from day 2 through week 6, and neutrophils at day 2-4. Increased collagen volume fraction, presenting as immature scars associated with fibroblast clusters and interstitial/perivascular fibrosis, was evident on day 14 in both ventricles. In contrast, fibroblast proliferation during aldosterone infusion did not appear in both ventricles until week 3 and was associated with a subsequent reparative and reactive fibrosis as early as 4 weeks. Myofibroblasts became evident between 3-6 weeks; macrophages and lymphocytes were seen between 3-8 weeks. Neutrophils were not seen at any time point with aldosterone. Thus, the temporal cellular response and appearance of myocardial fibrosis associated with chronic elevations in angiotensin II and/or aldosterone differ. We conclude that separate pathogenic mechanisms are operative with these effector hormones of the RAAS.
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PMID:Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone. 852 18

An intracardiac aldosterone system which responds to short- and long-term physiological stimuli has been described. This cardiac generated aldosterone has possibly autocrine or paracrine actions. Normal cardiac tissue contains mineralocorticoid receptors (MR) and cardiac high affinity MR are localized in cardiac myocytes and endothelial cells. Data concerning the presence of MR in cardiac fibroblasts are, however, controversial. MR are not specific for aldosterone but they also bind glucocorticoids. Cardiac fibroblasts however contain the enzyme 11beta-hydroxy-steroid dehydrogenase II which converts these glucocorticoids to inactive metabolites. Discordant findings on the in vitro effect of aldosterone on the collagen synthesis in cardiac fibroblasts are reported and can at least partly attributed to the presence of various fibroblasts phenotypes. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. This cardiac fibrosis in this aldosteronism model is prevented by spironolactone. This effect of aldosterone is crucially dependent on the salt status of the rat. Indeed, rats on a restricted salt intake infused with aldosterone had no cardiac fibrosis above control levels. During the continuous infusion of aldosterone in the rat the appearance of fibrosis was delayed and starts 4 weeks after the beginning of the infusion which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1 receptors and the cardiac AT1 receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin-angiotensin-aldosterone system such as in surgically induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure spironolactone treatment in addition to diuretics and angiotensin-converting enzyme (ACE) inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III-IV reduces total mortality by 30%.
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PMID:Induction of cardiac fibrosis by aldosterone. 1088 42

The role of EGF in the evolution of renal lesions after injury is still controversial. To determine whether the EGF expression is beneficial or detrimental, we generated transgenic mice expressing a COOH-terminal-truncated EGF-R under the control of the kidney-specific type 1 gamma-glutamyl transpeptidase promoter. As expected, the transgene was expressed exclusively at the basolateral membrane of proximal tubular cells. Under basal conditions, transgenic mice showed normal renal morphology and function. Infusion of EGF to transgenic animals revealed that the mutant receptor behaved in a dominant-negative manner and prevented EGF-signaled EGF-R autophosphorylation. We next evaluated the impact of transgene expression on the development of renal lesions in two models of renal injury. After 75% reduction of renal mass, tubular dilations were less severe in transgenic mice than in wild-type animals. After prolonged renal ischemia, tubular atrophy and interstitial fibrosis were reduced in transgenic mice as compared with wild-type mice. The beneficial effect of the transgene included a reduction of tubular cell proliferation, interstitial collagen accumulation, and mononuclear cell infiltration. In conclusion, functional inactivation of the EGF-R in renal proximal tubular cells reduced tubulo-interstitial lesions after renal injury. These data suggest that blocking the EGF pathway may be a therapeutic strategy to reduce the progression of chronic renal failure.
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PMID:Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury. 1090 38

We investigated the influence of myocardial collagen volume fraction (CVF, %) and hydroxyproline concentration (microg/mg) on rat papillary muscle function. Collagen excess was obtained in 10 rats with unilateral renal ischemia for 5 wk followed by 3-wk treatment with ramipril (20 mg. kg(-1). day(-1)) (RHTR rats; CVF = 3.83 +/- 0. 80, hydroxyproline = 3.79 +/- 0.50). Collagen degradation was induced by double infusion of oxidized glutathione (GSSG rats; CVF = 2.45 +/- 0.52, hydroxyproline = 2.85 +/- 0.18). Nine untreated rats were used as controls (CFV = 3.04 +/- 0.58, hydroxyproline = 3.21 +/- 0.30). Active stiffness (AS; g. cm(-2). %L(max)(-1)) and myocyte cross-sectional area (MA; micrometer(2)) were increased in the GSSG rats compared with controls [AS 5.86 vs. 3.96 (P < 0.05); MA 363 +/- 59 vs. 305 +/- 28 (P < 0.05)]. In GSSG and RHTR groups the passive tension-length curves were shifted downwards, indicating decreased passive stiffness, and upwards, indicating increased passive stiffness, respectively. Decreased collagen content induced by GSSG is related to myocyte hypertrophy, decreased passive stiffness, and increased AS, and increased collagen concentration causes myocardial diastolic dysfunction with no effect on systolic function.
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PMID:Alterations in myocardial collagen content affect rat papillary muscle function. 1100 38

TGF-beta1 has been demonstrated to be up-regulated in response to ischemic events both in animal models and in man. Demonstration of this up-regulation in the kidney following experimentally induced acute renal failure and in renal transplants complements similar findings in coronary and cerebral ischemia. Activation of TGF-beta1 occurs as a direct consequence of hypoxia, angiotensin II signaling and loss of extra cellular matrix (ECM) integrity, all of which occur in renal ischemia-reperfusion injury. TGF-beta1 thus up-regulates the synthesis of extracellular matrix components such as fibronectin and collagen IV providing a basis for the restoration of epithelial coverage in the regenerating tubule. TGF-beta1 also regulates epithelial tubular cell proliferation and differentiation. This response is quickly closed down in response to recovery of the kidney. This review examines the evidence linking TGF-beta1 activity to recovery from renal ischemia thereby constructing a hypothesis for the beneficial role of TGF-beta1 in the post ischemic kidney.
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PMID:Transforming growth factor-beta1 (TGF-beta1): a potential recovery signal in the post-ischemic kidney. 1221 20


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