33 research outputs found
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Ferric Citrate Attenuates Cardiac Hypertrophy and Fibrosis in a Rat Model of Chronic Kidney Disease.
IntroductionChronic kidney disease (CKD) promotes hypertrophy and fibrosis in heart, and increases the risk of cardiovascular mortality. Ferric citrate is a dietary phosphate binder used to control hyperphosphatemia in CKD patients. It has been shown to raise iron stores, improve anemia and secondary hyperparathyroidism, and decrease vascular calcification in CKD patients. The present study was done to explore the effects and mechanism of actions of ferric citrate on cardiac hypertrophy and fibrosis.Materials and methodsMale SD rats were randomized to CKD (5/6 nephrectomized) and sham-operated control groups. CKD rats were fed regular diet or a diet containing 4% ferric citrate. After 8 weeks, hemoglobin, renal function and cardiovascular endpoints including blood pressure, heart/body weight ratio, serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP), cardiac histology and markers of hypertrophy, fibrosis and inflammation were assessed.ResultsCompared to the controls, untreated CKD group exhibited hypertension, elevated serum urea, creatinine, phosphate, and NT-proBNP concentrations, anemia, cardiomegaly ,cardiac hypertrophy and fibrosis. Treatment with ferric citrate significantly increased hemoglobin and serum iron concentrations, reduced serum phosphate and NT-proBNP levels and ameliorated hypertension, heart/body weight ratio, cardiac hypertrophy, fibrosis and inflammation. In addition, ferric citrate administration reduced the size of cardiomyocytes and expressions of myocardin, transforming growth factor-β, interleukin-6 and monocyte chemotactic protein 1.ConclusionsTreatment with ferric citrate attenuated renal failure and cardiovascular abnormalities including myocardial hypertrophy and fibrosis in CKD rats
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Uremia induces upregulation of cerebral tissue oxidative/inflammatory cascade, down-regulation of Nrf2 pathway and disruption of blood brain barrier.
Chronic kidney disease (CKD) results in various central nervous systems (CNS) disorders including cognitive dysfunction, depression, anxiety, movement disorders, seizures and encephalopathy. Uremic retention products, oxidative stress, inflammation and impaired blood-brain barrier have been implicated as the major mediators of CKD-induced CNS disorders. However, mechanisms of CKD-induced cerebral tissue oxidative stress, inflammation and impaired blood brain barrier have not been fully elucidated and were explored. Male Sprague Dawley rats underwent sham operation or 5/6 nephrectomy and were observed for 10 weeks. Arterial pressure, body weight, and renal function were monitored. Under general anesthesia the animals' cerebral cortex was harvested. Nuclear translocations of NF-κB and Nrf2 and their key target gene products, neuronal, endothelial and inducible NO synthase (NOS) isoforms, markers of oxidative, nitrosative and myeloperoxidase reactions, fibrosis mediators and key protein constituents of capillary endothelial junctional complex were determined by Western blot analysis. The CKD rats exhibited reduced body weight, hypertension, elevated serum urea and creatinine concentrations. Compared to control group cerebral cortex of the CKD group showed activation (increased nuclear translocation) of NF-κB, elevation of pro-oxidant and pro-inflammatory molecules, diminished nuclear translocation of Nrf2 and expression of cytoprotective antioxidant molecules and depletion of the key protein constituents of endothelial junctional complex. In conclusion CKD results in the cerebral tissue activation of inflammatory and oxidative pathways, inhibition of antioxidant and cytoprotective system and erosion of cerebral capillary junctional complex, events that contribute to CNS dysfunction and impaired blood brain barrier
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Uremia induces upregulation of cerebral tissue oxidative/inflammatory cascade, down-regulation of Nrf2 pathway and disruption of blood brain barrier.
Chronic kidney disease (CKD) results in various central nervous systems (CNS) disorders including cognitive dysfunction, depression, anxiety, movement disorders, seizures and encephalopathy. Uremic retention products, oxidative stress, inflammation and impaired blood-brain barrier have been implicated as the major mediators of CKD-induced CNS disorders. However, mechanisms of CKD-induced cerebral tissue oxidative stress, inflammation and impaired blood brain barrier have not been fully elucidated and were explored. Male Sprague Dawley rats underwent sham operation or 5/6 nephrectomy and were observed for 10 weeks. Arterial pressure, body weight, and renal function were monitored. Under general anesthesia the animals' cerebral cortex was harvested. Nuclear translocations of NF-κB and Nrf2 and their key target gene products, neuronal, endothelial and inducible NO synthase (NOS) isoforms, markers of oxidative, nitrosative and myeloperoxidase reactions, fibrosis mediators and key protein constituents of capillary endothelial junctional complex were determined by Western blot analysis. The CKD rats exhibited reduced body weight, hypertension, elevated serum urea and creatinine concentrations. Compared to control group cerebral cortex of the CKD group showed activation (increased nuclear translocation) of NF-κB, elevation of pro-oxidant and pro-inflammatory molecules, diminished nuclear translocation of Nrf2 and expression of cytoprotective antioxidant molecules and depletion of the key protein constituents of endothelial junctional complex. In conclusion CKD results in the cerebral tissue activation of inflammatory and oxidative pathways, inhibition of antioxidant and cytoprotective system and erosion of cerebral capillary junctional complex, events that contribute to CNS dysfunction and impaired blood brain barrier
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LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD.
Progressive deterioration of kidney function in chronic kidney disease (CKD) is mediated by hypertension, oxidative stress, inflammation, and fibrosis. Renin-angiotensin blockade is commonly used to retard CKD progression. In addition, vasoactive peptides have been shown to reduce blood pressure and exert antioxidant, anti-inflammatory and anti-fibrotic effects. We hypothesized that administration of LCZ696 (sacubitril/valsartan) is more effective than valsartan alone in slowing progression of CKD. Male Sprague Dawley rats underwent sham surgery or 5/6 nephrectomy and after two weeks the CKD animals were randomized to no treatment, valsartan (30 mg/kg), or LCZ696 (60 mg/kg) daily by gavage. Serum, urine and kidney tissue analyses were performed after 8 weeks. The untreated CKD rats exhibited hypertension, proteinuria, tubular and glomerular damage, upregulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways; reduction in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its key target products. LCZ696 administration improved renal function and histology and attenuated most of the molecular markers of oxidative stress, inflammation and fibrosis. Furthermore, LCZ696 was more effective than valsartan therapy alone in delaying the progression of kidney disease. Future clinical trials are needed to determine the safety and efficacy of this agent in treatment of patients with CKD
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LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD.
Progressive deterioration of kidney function in chronic kidney disease (CKD) is mediated by hypertension, oxidative stress, inflammation, and fibrosis. Renin-angiotensin blockade is commonly used to retard CKD progression. In addition, vasoactive peptides have been shown to reduce blood pressure and exert antioxidant, anti-inflammatory and anti-fibrotic effects. We hypothesized that administration of LCZ696 (sacubitril/valsartan) is more effective than valsartan alone in slowing progression of CKD. Male Sprague Dawley rats underwent sham surgery or 5/6 nephrectomy and after two weeks the CKD animals were randomized to no treatment, valsartan (30 mg/kg), or LCZ696 (60 mg/kg) daily by gavage. Serum, urine and kidney tissue analyses were performed after 8 weeks. The untreated CKD rats exhibited hypertension, proteinuria, tubular and glomerular damage, upregulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways; reduction in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its key target products. LCZ696 administration improved renal function and histology and attenuated most of the molecular markers of oxidative stress, inflammation and fibrosis. Furthermore, LCZ696 was more effective than valsartan therapy alone in delaying the progression of kidney disease. Future clinical trials are needed to determine the safety and efficacy of this agent in treatment of patients with CKD
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LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease.
BackgroundChronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. LCZ696 (sacubitril/valsartan) is a promising agent that has shown significant potential in treatment of heart failure. We hypothesized that LCZ696 is more effective than valsartan alone in the treatment of cardiovascular abnormalities associated with experimental CKD.Methods and resultsMale Sprague-Dawley rats underwent 5/6 nephrectomy and were subsequently randomized to no treatment (CKD), 30 mg/kg valsartan (VAL), or 60 mg/kg LCZ696 (LCZ). After 8 weeks, cardiovascular parameters, including markers of inflammation, oxidative stress, mitochondrial abundance/function, hypertrophy, and fibrosis, were measured. Treatment with LCZ resulted in significant improvements in the heart-body weight ratio and serum concentrations of N-terminal pro-B-type natriuretic peptide and fibroblast growth factor 23 along with improvement of kidney function. In addition, LCZ ameliorated aortic fibrosis and cardiac hypertrophy and fibrosis, reduced markers of cardiac oxidative stress and inflammation, and improved indicators of mitochondrial mass/function. Although VAL also improved some of these indices, treatment with LCZ was more effective than VAL alone.ConclusionsCKD-associated cardiovascular abnormalities, including myocardial hypertrophy, fibrosis, inflammation, oxidative stress, and mitochondrial depletion/dysfunction, were more effectively attenuated by LCZ treatment than by VAL alone