endothelin-1 and Atrophy

Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Atrophy; Cicatrix; Connective Tissue Growth Factor; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Humans; Hypoxia; Models, Cardiovascular; Molecular Targeted Therapy; Myocardium; Myofibroblasts; Platelet-Derived Growth Factor; Pyridones; Rats; Signal Transduction; Transforming Growth Factor beta

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.

Topics: Animals; Animals, Newborn; Association Learning; Atrophy; Brain Ischemia; Cell Count; Cerebral Cortex; Cerebral Palsy; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Endothelin-1; Inflammation; Injections; Microglia; Movement Disorders; Neurons; Perceptual Disorders; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Vasoconstrictor Agents; White Matter

Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and β-amyloid (Aβ) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Aβ toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Aβ. Gross morphologic changes in comorbid Aβ and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Aβ precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear-conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when Aβ toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Atrophy; Connexin 43; Dementia; Disease Models, Animal; Endothelin-1; Hippocampus; Humans; Injections, Intraventricular; Male; Stroke; Vasoconstrictor Agents

Functional studies have shown that orchidectomy increases the effects of phenylephrine on rat portal veins, but that it is completely prevented in the presence of both ETA and ETB receptor antagonists. Although it suggests the involvement of endothelin-1 (ET-1), the local production of this vasoactive peptide has not been directly quantified in portal veins. Therefore, the aim of the present study was to verify if orchidectomy increases the local expression of ET-1 as well as ETA and ETB receptors in the rat portal vein. Indeed, the genic expression of ET-1, ETA and ETB receptors in rat portal veins taken from control (CONT), orchidectomized (ORX) and ORX plus testosterone-replacement therapy (ORX + T) animals were determined by Real Time RT-PCR. The results showed that orchidectomy induced a significant increment in genic expression of ET-1 and ETB receptors in the rat portal veins, which was completely reversed by testosterone replacement treatment. In conclusion, the results suggest that orchidectomy increases the production of ET-1 in the rat portal vein and that, at least partially, it may be related to the previously reported elevation of responses to phenylephrine.

Topics: Animals; Atrophy; Endothelin-1; Gene Expression; Male; Orchiectomy; Portal Vein; Prostate; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Seminal Vesicles; Testosterone

To investigate the expression of endothelin-1 (ET-1) and adrenomedullin (ADM) in the renal pelvis, stenotic ureteropelvic junction, and ureter of 20 male Wistar rats with congenital unilateral ureteropelvic junction obstruction; the normal contralateral kidneys served as controls. The molecular pathophysiology of congenital ureteropelvic junction obstruction is still unclear. The implication of altered peptidergic innervation is under discussion. Our study group has recently been able to demonstrate a significant increase in ET-1 and a significant decrease in ADM in prestenotic and stenotic tissue, but not in the remainder of the ureter, compared with controls.. Twenty animals were killed, and samples of the renal pelvis, ureteropelvic junction, upper ureter, middle part of the ureter, and lower ureter were immediately snap-frozen and stored in liquid nitrogen. Total RNA was extracted, and subsequently 1 microg of RNA was reversely transcribed. mRNA expression of ET-1 and ADM was determined semiquantitatively using on-line polymerase chain reaction. The expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was determined to relate the specific mRNA expression to the expression of a housekeeping gene.. We found a significant increase in the expression of ET-1 in the obstructed junctions related to GAPDH (P <0.001). The expression of ADM, however, revealed no statistically significant differences. No differences at all could be detected in the tissue samples from the rest of the ureter.. Alterations in the local production of peptidergic neurotransmitters, especially ET-1, may contribute to the molecular pathogenesis of ureteropelvic junction obstruction. Results previously obtained in the stenotic tissue from children were confirmed in the stenotic tissue from the rat model. We hypothesize that the alterations are disease-, but not age-specific.

Topics: Abnormalities, Multiple; Adrenomedullin; Animals; Atrophy; Computer Systems; Constriction, Pathologic; Disease Models, Animal; Endothelin-1; Gene Expression Profiling; Hydronephrosis; Kidney Pelvis; Male; Peptides; Polymerase Chain Reaction; Rats; Rats, Mutant Strains; Rats, Wistar; RNA, Messenger; Ureter; Ureteral Obstruction

The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-kappaB (NF-kappaB), which regulates the transcription of many genes involved in renal injury, could be implicated. In rats with intense proteinuria, we studied the renal activation of NF-kappaB as well as the potential involvement of the vasoactive hormones angiotensin II (Ang II) and endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1 g/d of BSA had proteinuria but no renal morphological lesions at day 1. By contrast, tubular atrophy and/or dilation and mononuclear cell infiltration were observed after 8 or 28 days of BSA administration, coinciding with maximal proteinuria. In relation to control uninephrectomized rats, the renal cortex of nephritic rats showed an increment in the activation of NF-kappaB at all time periods studied. By in situ Southwestern histochemistry, NF-kappaB activity was mainly localized in proximal tubules, interstitial mononuclear cells, and, to a lesser extent, the glomeruli. The administration of the ACE inhibitor quinapril plus the ET(A)/ET(B) receptor antagonist bosentan during 28 days to BSA-overloaded animals diminished proteinuria, renal lesions, and NF-kappaB activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-kappaB activation in a time- and dose-dependent manner. Incubation of cells with receptor antagonists of Ang II (AT(1): losartan and AT(2): PD-123,319) or ET-1 (ET(A): BQ123 and ET(B): IRL1038) inhibited significantly the BSA-induced NF-kappaB activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-kappaB activation in tubular epithelial cells both in vivo and in vitro. The vasoactive peptides Ang II and ET-1 appear to be implicated in this effect. The results reveal a novel mechanism of perpetuation of renal damage induced by persistent proteinuria.

Topics: Analysis of Variance; Angiotensin II; Animals; Atrophy; Cell Line; Endothelin-1; Epithelial Cells; Female; Kidney Cortex; Kidney Tubules; Nephrectomy; Nephritis; NF-kappa B; Proteinuria; Rats; Rats, Inbred WKY

Topics: Adult; Atrophy; Endothelin-1; Endothelins; Female; Fibrosis; Hormone Antagonists; Humans; Kidney; Kidney Diseases; Kidney Tubules; RNA, Messenger

Chronic pressure overload is known to increase cardiac mass and expression levels of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs. Although mechanical stretching of cardiac myocytes could cause these changes, humoral factor(s) secondary to pressure overload may also be involved. To dissociate humoral effects from the effects of mechanical loading on cardiac hypertrophic responses, we examined expression of ANP and BNP at both mRNA and protein levels and proportions of myosin isoforms in transplanted cervical hearts that were mechanically unloaded under conditions with or without hypertension by aortic coarctation. Seven days after transplantation, cardiac atrophy that usually occurs in transplanted hearts without hypertension by coarctation was prevented in the transplanted hearts with hypertension by coarctation. The levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts with relative to those without hypertension by coarctation. The plasma level of angiotensin II was higher in rats with than without hypertension by coarctation. Plasma endothelin-1 levels were not significantly different between the two groups. In addition, levels of expression of ANP and BNP mRNAs were increased in the transplanted hearts without hypertension relative to those in the in situ hearts. The proportion of the V3 myosin isoform was also increased in the transplanted hearts without hypertension relative to the in situ hearts. These results indicate that humoral factor(s) secondary to the pressure overload produced by aortic coarctation enhanced the cardiac hypertrophic response and elevated the levels of mRNAs encoding these embryonic markers. Moreover, our findings regarding ANP and BNP expression in the transplanted hearts provide additional evidence that the fetal genes are reexpressed during the process of cardiac atrophy as well as in cardiac hypertrophy.

Topics: Angiotensin II; Animals; Aortic Coarctation; Atrial Natriuretic Factor; Atrophy; Blood Pressure; Body Weight; Cardiomegaly; Endothelin-1; Heart Rate; Heart Transplantation; Hypertension; Male; Myosins; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Rats; Rats, Inbred Lew; RNA, Messenger; Transcription, Genetic; Transplantation, Heterotopic; Transplantation, Isogeneic