The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
Qing Zhu - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of microRNA-429 in the Renal Medulla increased salt sensitivity of blood pressure in Sprague Dawley rats.
Journal of hypertension, 2017Co-Authors: Qing Zhu, Zhengchao Wang, Lei Wang, Weili Wang, Krishna M BoiniAbstract:Background We have previously shown that high salt intake suppresses the expression of prolyl hydroxylase domain-containing protein 2 (PHD2), an enzyme promoting the degradation of hypoxia-inducible factor (HIF)-1α, and increases HIF-1α along with its target genes in the Renal Medulla, which promotes sodium excretion and regulates salt sensitivity of blood pressure. However, it remains unknown how high salt inhibits the expression of PHD2. Method and results The current study first revealed that high-salt-induced PHD2 inhibition was due to the enhanced decay of mRNA. We then found that high salt significantly increased the expression of miR-429, which was subsequently proven to target the 3'-untranslated region of PHD2 and reduce PHD2 levels, in the Renal Medulla. To define the functional role of Renal Medullary miR-429 in the regulation of PHD2/HIF-1α-mediated Renal adaptation to high salt intake and salt sensitivity of blood pressure, we locally inhibited miR-429 in the Renal Medulla by locked nucleic acid anti-miR-429 in uninephrectomized rats. Our results demonstrated that inhibition of miR-429 remarkably increased the levels of PHD2, which disrupted PHD2-associated adaptive activation of HIF-1α-mediated gene expression in response to high salt in the Renal Medulla and consequently inhibited urinary sodium excretion, enhanced sodium retention in response to chronic sodium overloading, and as a result, produced a salt-sensitive hypertension. Conclusion It is concluded that miR-429 is an important upstream mediator in PHD2/HIF-1α-associated Renal adaptation to high salt intake and that deficiency in miR-429-mediated PHD2 inhibition in response to high salt in the Renal Medulla may represent a pathogenic mechanism for salt-sensitive hypertension.
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Mesenchymal stem cell transplantation inhibited high salt-induced activation of the NLRP3 inflammasome in the Renal Medulla in Dahl S rats.
American journal of physiology. Renal physiology, 2016Co-Authors: Qing Zhu, Weili Wang, Sabena Michelle ConleyAbstract:Inflammasomes activate caspase-1 to produce interleukin (IL)-1β. Activation of the NLRP3 inflammasome is involved in various Renal pathological conditions. It remains unknown whether the NLRP3 inflammasome activation participates in the abnormal Renal response to high-salt (HS) diet in Dahl salt-sensitive (S) rats. In addition, our lab recently showed that transplantation of mesenchymal stem cells (MSCs) attenuated HS-induced inflammation in the Renal Medulla in Dahl S rat. However, it is unclear whether the anti-inflammatory action of MSCs is associated with inhibition of the NLRP3 inflammasome. The present study determined the response of the NLRP3 inflammasome to HS intake and the effect of MSC transplantation on the NLRP3 inflammasome in the Renal Medulla in Dahl S rats. Immunostaining showed that the inflammasome components NLRP3, ASC, and caspase-1 were mainly present in distal tubules and collecting ducts. Interestingly, the Renal Medullary levels of these inflammasome components were remarkably increased after a HS diet in Dahl S rats, while remaining unchanged in normal rats. This HS-induced activation of the NLRP3 inflammasome was significantly blocked by MSC transplantation into the Renal Medulla in Dahl S rats. Furthermore, infusion of a caspase-1 inhibitor into the Renal Medulla significantly attenuated HS-induced hypertension in Dahl S rats. These data suggest that HS-induced activation of the NLRP3 inflammasome may contribute to Renal Medullary dysfunction in Dahl S rats and that inhibition of inflammasome activation may be one of the mechanisms for the anti-inflammatory and anti-hypertensive effects of stem cells in the Renal Medulla in Dahl S rats.
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Silencing of HIF prolyl-hydroxylase 2 gene in the Renal Medulla attenuates salt-sensitive hypertension in Dahl S rats.
American journal of hypertension, 2013Co-Authors: Qing Zhu, Fan Zhang, Wei-qing Han, Zhengchao WangAbstract:Salt-sensitive hypertension accounts for 50% of hypertension cases1 and exhibits a much higher risk for development of organ damage than salt-resistant hypertension.2,3 The mechanism regulating salt sensitivity of blood pressure is not very clear. Renal Medullary function is well known to play a critical role in the regulation of sodium excretion and blood pressure, and it is known that dysfunction in the Renal Medulla is involved in salt-sensitive hypertension.4,5 We have recently shown that transcription factor hypoxia-inducible factor (HIF) 1α–mediated activation of antihypertensive genes in the Renal Medulla enhances the production of a variety of protective factors in the Renal Medulla, which promotes the excretion of extra sodium load and regulates the Renal adaptation to high salt intake.6 HIF-1α and many HIF-1α target genes, such as hemeoxygenase 1 (HO-1), cyclooxygenase 2 (COX-2), nitric oxide synthase 2 (NOS-2), and endothelin 1, are highly expressed in the Renal Medulla and significantly upregulated in response to high salt intake.7–13 The products of these HIF-1α target genes importantly participate in the regulation of blood flow and/or tubular activity in the Renal Medulla and play critical roles in sodium balance and long-term control of arterial blood pressure as well as salt sensitivity of blood pressure.7,8,11–15 We have demonstrated that high salt diet upregulates HIF-1α levels in the Renal Medulla6,16 and that blockade of HIF-1α function to inhibit the expression of its target genes in the Renal Medulla induces sodium retention after high-salt challenge, producing a salt-sensitive hypertension.6 These results suggest that HIF-1α–mediated gene activation in the Renal Medulla represents an important molecular adaptive mechanism to maintain sodium balance in response to high salt intake. Interestingly, it has been shown that the above protective genes regulated by HIF-1α are defective in Dahl salt-sensitive hypertensive (Dahl S) rats12,13,16–18 and that the deficiencies of these HIF-1α target genes in the Renal Medulla are considered to be responsible for the development of hypertension in this animal model.12,13,17 We recently showed that upregulation of Renal Medullary HIF-1α levels in response to high salt intake was blunted in Dahl S rats,16,19 indicating that the abnormal responses of the above protective genes may be due to a defect of HIF-1α in the Renal Medulla and that impairment in HIF-1α–mediated gene activation in the Renal Medulla may be responsible for salt-sensitive hypertension in Dahl S rats. Indeed, correction of HIF-1α deficiency in the Renal Medulla increased the expression of antihypertensive genes in the Renal Medulla, enhanced the urinary sodium excretion, reduced sodium retention, and consequently, attenuated salt-sensitive hypertension in Dahl S rats.19 Furthermore, it has been demonstrated that HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1α, is the most abundant isoform of PHDs in the kidneys20,21 and is highly expressed in the Renal Medulla.16,20,21 We have shown that high salt intake suppresses the expression of PHD2 in the Renal Medulla and that this high salt–induced inhibition of PHD2 is an upstream signal that increases HIF-1α–mediated gene expression in the Renal Medulla in response to high-salt challenge.16 Notably, the high salt–induced inhibition in PHD2 in the Renal Medulla is also defective in Dahl S rats.16 This study sought to test the hypothesis that deficiency in PHD2/HIF-1α–mediated molecular adaptation in response to high salt intake in the Renal Medulla may be the pathogenic mechanism responsible for salt-sensitive hypertension and that silencing the PHD2 gene to increase the levels of HIF-1α and its target genes in the Renal Medulla enhances the sodium excretion and attenuates salt-sensitive hypertension in Dahl S rats. We first transfected PHD2 short hairpin RNA (shRNA) plasmids into the Renal Medulla and then detected the pressure natriuresis, the Renal sodium excretion after sodium overload, and the arterial blood pressure after high-salt challenge in Dahl S rats. Our data showed that correction of the defect in PHD2 response to high salt intake attenuated salt-sensitive hypertension in Dahl S rats.
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Overexpression of HIF prolyl-hydoxylase-2 transgene in the Renal Medulla induced a salt sensitive hypertension.
Journal of cellular and molecular medicine, 2012Co-Authors: Qing Zhu, Wei-qing Han, Miao Liu, Zhengchao WangAbstract:Renal Medullary hypoxia-inducible factor (HIF)-1α and its target genes, such as haem oxygenase and nitric oxide synthase, have been indicated to play an important role in the regulation of sodium excretion and blood pressure. HIF prolyl hydroxylase domain-containing proteins (PHDs) are major enzymes to promote the degradation of HIF-1α. We recently reported that high salt intake suppressed the Renal Medullary PHD2 expression and thereby activated HIF-1α-mediated gene regulation in the Renal Medulla in response to high salt. To further define the functional role of Renal Medullary PHD2 in the regulation of Renal adaptation to high salt intake and the longer term control of blood pressure, we transfected PHD2 expression plasmids into the Renal Medulla in uninephrectomized rats and determined its effects on pressure natriuresis, sodium excretion after salt overloading and the long-term control of arterial pressure after high salt challenge. It was shown that overexpression of PHD2 transgene increased PHD2 levels and decreased HIF-1α levels in the Renal Medulla, which blunted pressure natriuresis, attenuated sodium excretion, promoted sodium retention and produced salt sensitive hypertension after high salt challenge compared with rats treated with control plasmids. There was no blood pressure change in PHD2-treated rats that were maintained in low salt diet. These results suggested that Renal Medullary PHD2 is an important regulator in Renal adaptation to high salt intake and a deficiency in PHD2-mediated molecular adaptation in response to high salt intake in the Renal Medulla may represent a pathogenic mechanism producing salt sensitive hypertension.
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Abstract 35: Transplantation of Mesenchymal Stem Cells into the Renal Medulla Attenuated Salt-sensitive Hypertension in Dahl S Rat
Hypertension, 2012Co-Authors: Qing Zhu, Wei-qing HanAbstract:Transplantation of mesenchymal stem cells (MSCs) has been employed as a therapeutic strategy for many different diseases. We have recently shown that there is a stem cell dysfunction in the Renal Medulla that may contribute to the development of salt-sensitive hypertension in Dahl S rats. The present study tested the hypothesis that transplantation of MSCs into the Renal Medulla improves salt-sensitive hypertension in Dahl S rats. Rat adult MSCs were obtained from Texas A&M Health Science Center, ex-vivo expanded and infused (5 million cells) into the Renal Medulla in uninephrectomized Dahl S rats, which were then treated with low salt (LS, 0.4% NaCl) or high salt (HS, 8% NaCl) diet for 10 days. Results showed that the mRNA levels of stem cell markers CD133 and CD90 were increased by 60% and 70%, respectively, in the Renal Medulla in MSC-treated rats compared with control cell-treated rats. HS challenge increased mean arterial blood pressure in control cell-treated animals (from 113.9 ± 3.4 to 153.5 ± 4.8 mmHg), which was significantly attenuated in MSC-treated animals (from 114.1 ± 3.5 to 131.3 ± 2.5 mmHg). Meanwhile, ELISA analysis showed that the levels of pro-inflammatory cytokine interleukin-1β in the Renal Medulla were remarkably increased in HS-treated rats compared with LS-treated rats, which was blocked in MSC-treated rats (1.81 ± 0.18 ng/mg protein in LS group, 2.84 ± 0.57 in HS +control cell and 1.83 ± 0.35 in HS+MSC). Furthermore, immunostaining showed that the significant increase in immune cell (CD43+) infiltration into the Renal Medulla in HS control rats was reduced in HS+MSC rats. These results suggest that correction of stem cell dysfunction in the Renal Medulla attenuated inflammation in this kidney region after HS challenge and improved high salt-induced hypertension in Dahls S rats, which may serve as a therapeutic approach for salt-sensitive hypertension (supported by NIH grant HL89563 and HL106042)
Zhengchao Wang - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of microRNA-429 in the Renal Medulla increased salt sensitivity of blood pressure in Sprague Dawley rats.
Journal of hypertension, 2017Co-Authors: Qing Zhu, Zhengchao Wang, Lei Wang, Weili Wang, Krishna M BoiniAbstract:Background We have previously shown that high salt intake suppresses the expression of prolyl hydroxylase domain-containing protein 2 (PHD2), an enzyme promoting the degradation of hypoxia-inducible factor (HIF)-1α, and increases HIF-1α along with its target genes in the Renal Medulla, which promotes sodium excretion and regulates salt sensitivity of blood pressure. However, it remains unknown how high salt inhibits the expression of PHD2. Method and results The current study first revealed that high-salt-induced PHD2 inhibition was due to the enhanced decay of mRNA. We then found that high salt significantly increased the expression of miR-429, which was subsequently proven to target the 3'-untranslated region of PHD2 and reduce PHD2 levels, in the Renal Medulla. To define the functional role of Renal Medullary miR-429 in the regulation of PHD2/HIF-1α-mediated Renal adaptation to high salt intake and salt sensitivity of blood pressure, we locally inhibited miR-429 in the Renal Medulla by locked nucleic acid anti-miR-429 in uninephrectomized rats. Our results demonstrated that inhibition of miR-429 remarkably increased the levels of PHD2, which disrupted PHD2-associated adaptive activation of HIF-1α-mediated gene expression in response to high salt in the Renal Medulla and consequently inhibited urinary sodium excretion, enhanced sodium retention in response to chronic sodium overloading, and as a result, produced a salt-sensitive hypertension. Conclusion It is concluded that miR-429 is an important upstream mediator in PHD2/HIF-1α-associated Renal adaptation to high salt intake and that deficiency in miR-429-mediated PHD2 inhibition in response to high salt in the Renal Medulla may represent a pathogenic mechanism for salt-sensitive hypertension.
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transplantation of mesenchymal stem cells into the Renal Medulla attenuated salt sensitive hypertension in dahl s rat
Journal of Molecular Medicine, 2014Co-Authors: Junping Hu, Zhengchao Wang, Pinlan Li, Fan Yi, Ningjun LiAbstract:Adult stem cell deficiency has been implicated in the pathogenic mechanism for various diseases. Renal Medullary dysfunction is one of the major mechanisms for the development of hypertension in Dahl salt-sensitive (S) rats. The present study first detected a stem cell deficiency in the Renal Medulla in Dahl S rats and then tested the hypothesis that transplantation of mesenchymal stem cells (MSCs) into the Renal Medulla improves salt-sensitive hypertension in Dahl S rats. Immunohistochemistry and flowcytometry analyses showed a significantly reduced number of stem cell marker CD133+ cells in the Renal Medulla from Dahl S rats compared with controls, suggesting a stem cell deficiency. Rat MSCs or control cells were transplanted into the Renal Medulla in uninephrectomized Dahl S rats, which were then treated with a low- or high-salt diet for 20 days. High-salt-induced sodium retention and hypertension was significantly attenuated in MSC-treated rats compared with control cell-treated rats. Meanwhile, high-salt-induced increases of proinflammatory factors, monocyte chemoattractant protein-1, and interleukin-1β, in the Renal Medulla were blocked by MSC treatment. Furthermore, immunostaining showed that high-salt-induced immune cell infiltration into the Renal Medulla was substantially inhibited by MSC treatment. These results suggested that stem cell defect in the Renal Medulla may contribute to the hypertension in Dahl S rats and that correction of this stem cell defect by MSCs attenuated hypertension in Dahl S rats through anti-inflammation.
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Silencing of HIF prolyl-hydroxylase 2 gene in the Renal Medulla attenuates salt-sensitive hypertension in Dahl S rats.
American journal of hypertension, 2013Co-Authors: Qing Zhu, Fan Zhang, Wei-qing Han, Zhengchao WangAbstract:Salt-sensitive hypertension accounts for 50% of hypertension cases1 and exhibits a much higher risk for development of organ damage than salt-resistant hypertension.2,3 The mechanism regulating salt sensitivity of blood pressure is not very clear. Renal Medullary function is well known to play a critical role in the regulation of sodium excretion and blood pressure, and it is known that dysfunction in the Renal Medulla is involved in salt-sensitive hypertension.4,5 We have recently shown that transcription factor hypoxia-inducible factor (HIF) 1α–mediated activation of antihypertensive genes in the Renal Medulla enhances the production of a variety of protective factors in the Renal Medulla, which promotes the excretion of extra sodium load and regulates the Renal adaptation to high salt intake.6 HIF-1α and many HIF-1α target genes, such as hemeoxygenase 1 (HO-1), cyclooxygenase 2 (COX-2), nitric oxide synthase 2 (NOS-2), and endothelin 1, are highly expressed in the Renal Medulla and significantly upregulated in response to high salt intake.7–13 The products of these HIF-1α target genes importantly participate in the regulation of blood flow and/or tubular activity in the Renal Medulla and play critical roles in sodium balance and long-term control of arterial blood pressure as well as salt sensitivity of blood pressure.7,8,11–15 We have demonstrated that high salt diet upregulates HIF-1α levels in the Renal Medulla6,16 and that blockade of HIF-1α function to inhibit the expression of its target genes in the Renal Medulla induces sodium retention after high-salt challenge, producing a salt-sensitive hypertension.6 These results suggest that HIF-1α–mediated gene activation in the Renal Medulla represents an important molecular adaptive mechanism to maintain sodium balance in response to high salt intake. Interestingly, it has been shown that the above protective genes regulated by HIF-1α are defective in Dahl salt-sensitive hypertensive (Dahl S) rats12,13,16–18 and that the deficiencies of these HIF-1α target genes in the Renal Medulla are considered to be responsible for the development of hypertension in this animal model.12,13,17 We recently showed that upregulation of Renal Medullary HIF-1α levels in response to high salt intake was blunted in Dahl S rats,16,19 indicating that the abnormal responses of the above protective genes may be due to a defect of HIF-1α in the Renal Medulla and that impairment in HIF-1α–mediated gene activation in the Renal Medulla may be responsible for salt-sensitive hypertension in Dahl S rats. Indeed, correction of HIF-1α deficiency in the Renal Medulla increased the expression of antihypertensive genes in the Renal Medulla, enhanced the urinary sodium excretion, reduced sodium retention, and consequently, attenuated salt-sensitive hypertension in Dahl S rats.19 Furthermore, it has been demonstrated that HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1α, is the most abundant isoform of PHDs in the kidneys20,21 and is highly expressed in the Renal Medulla.16,20,21 We have shown that high salt intake suppresses the expression of PHD2 in the Renal Medulla and that this high salt–induced inhibition of PHD2 is an upstream signal that increases HIF-1α–mediated gene expression in the Renal Medulla in response to high-salt challenge.16 Notably, the high salt–induced inhibition in PHD2 in the Renal Medulla is also defective in Dahl S rats.16 This study sought to test the hypothesis that deficiency in PHD2/HIF-1α–mediated molecular adaptation in response to high salt intake in the Renal Medulla may be the pathogenic mechanism responsible for salt-sensitive hypertension and that silencing the PHD2 gene to increase the levels of HIF-1α and its target genes in the Renal Medulla enhances the sodium excretion and attenuates salt-sensitive hypertension in Dahl S rats. We first transfected PHD2 short hairpin RNA (shRNA) plasmids into the Renal Medulla and then detected the pressure natriuresis, the Renal sodium excretion after sodium overload, and the arterial blood pressure after high-salt challenge in Dahl S rats. Our data showed that correction of the defect in PHD2 response to high salt intake attenuated salt-sensitive hypertension in Dahl S rats.
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Overexpression of HIF prolyl-hydoxylase-2 transgene in the Renal Medulla induced a salt sensitive hypertension.
Journal of cellular and molecular medicine, 2012Co-Authors: Qing Zhu, Wei-qing Han, Miao Liu, Zhengchao WangAbstract:Renal Medullary hypoxia-inducible factor (HIF)-1α and its target genes, such as haem oxygenase and nitric oxide synthase, have been indicated to play an important role in the regulation of sodium excretion and blood pressure. HIF prolyl hydroxylase domain-containing proteins (PHDs) are major enzymes to promote the degradation of HIF-1α. We recently reported that high salt intake suppressed the Renal Medullary PHD2 expression and thereby activated HIF-1α-mediated gene regulation in the Renal Medulla in response to high salt. To further define the functional role of Renal Medullary PHD2 in the regulation of Renal adaptation to high salt intake and the longer term control of blood pressure, we transfected PHD2 expression plasmids into the Renal Medulla in uninephrectomized rats and determined its effects on pressure natriuresis, sodium excretion after salt overloading and the long-term control of arterial pressure after high salt challenge. It was shown that overexpression of PHD2 transgene increased PHD2 levels and decreased HIF-1α levels in the Renal Medulla, which blunted pressure natriuresis, attenuated sodium excretion, promoted sodium retention and produced salt sensitive hypertension after high salt challenge compared with rats treated with control plasmids. There was no blood pressure change in PHD2-treated rats that were maintained in low salt diet. These results suggested that Renal Medullary PHD2 is an important regulator in Renal adaptation to high salt intake and a deficiency in PHD2-mediated molecular adaptation in response to high salt intake in the Renal Medulla may represent a pathogenic mechanism producing salt sensitive hypertension.
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Overexpression of HIF-1α transgene in the Renal Medulla attenuated salt sensitive hypertension in Dahl S rats
Biochimica et biophysica acta, 2012Co-Authors: Qing Zhu, Zhengchao Wang, Min Xia, Fan ZhangAbstract:Hypoxia inducible factor (HIF)-1α-mediated gene activation in the Renal Medulla in response to high salt intake plays an important role in the control of salt sensitivity of blood pressure. High salt-induced activation of HIF-1α in the Renal Medulla is blunted in Dahl S rats. The present study determined whether the impairment of the Renal Medullary HIF-1α pathway was responsible for salt sensitive hypertension in Dahl S rats. Renal Medullary HIF-1α levels were induced by either transfection of HIF-1α expression plasmid or chronic infusion of CoCl2 into the Renal Medulla, which was accompanied by increased expressions of anti-hypertensive genes, cyclooxygenase-2 and heme oxygenase-1. Overexpression of HIF-1α transgenes in the Renal Medulla enhanced the pressure natriuresis, promoted the sodium excretion and reduced sodium retention after salt overload. As a result, hypertension induced by 2-week high salt was significantly attenuated in rats treated with HIF-1α plasmid or CoCl2. These results suggest that an abnormal HIF-1α in the Renal Medulla may represent a novel mechanism mediating salt-sensitive hypertension in Dahl S rats and that induction of HIF-1α levels in the Renal Medulla could be a therapeutic approach for the treatment of salt-sensitive hypertension.
Wei-qing Han - One of the best experts on this subject based on the ideXlab platform.
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Silencing of HIF prolyl-hydroxylase 2 gene in the Renal Medulla attenuates salt-sensitive hypertension in Dahl S rats.
American journal of hypertension, 2013Co-Authors: Qing Zhu, Fan Zhang, Wei-qing Han, Zhengchao WangAbstract:Salt-sensitive hypertension accounts for 50% of hypertension cases1 and exhibits a much higher risk for development of organ damage than salt-resistant hypertension.2,3 The mechanism regulating salt sensitivity of blood pressure is not very clear. Renal Medullary function is well known to play a critical role in the regulation of sodium excretion and blood pressure, and it is known that dysfunction in the Renal Medulla is involved in salt-sensitive hypertension.4,5 We have recently shown that transcription factor hypoxia-inducible factor (HIF) 1α–mediated activation of antihypertensive genes in the Renal Medulla enhances the production of a variety of protective factors in the Renal Medulla, which promotes the excretion of extra sodium load and regulates the Renal adaptation to high salt intake.6 HIF-1α and many HIF-1α target genes, such as hemeoxygenase 1 (HO-1), cyclooxygenase 2 (COX-2), nitric oxide synthase 2 (NOS-2), and endothelin 1, are highly expressed in the Renal Medulla and significantly upregulated in response to high salt intake.7–13 The products of these HIF-1α target genes importantly participate in the regulation of blood flow and/or tubular activity in the Renal Medulla and play critical roles in sodium balance and long-term control of arterial blood pressure as well as salt sensitivity of blood pressure.7,8,11–15 We have demonstrated that high salt diet upregulates HIF-1α levels in the Renal Medulla6,16 and that blockade of HIF-1α function to inhibit the expression of its target genes in the Renal Medulla induces sodium retention after high-salt challenge, producing a salt-sensitive hypertension.6 These results suggest that HIF-1α–mediated gene activation in the Renal Medulla represents an important molecular adaptive mechanism to maintain sodium balance in response to high salt intake. Interestingly, it has been shown that the above protective genes regulated by HIF-1α are defective in Dahl salt-sensitive hypertensive (Dahl S) rats12,13,16–18 and that the deficiencies of these HIF-1α target genes in the Renal Medulla are considered to be responsible for the development of hypertension in this animal model.12,13,17 We recently showed that upregulation of Renal Medullary HIF-1α levels in response to high salt intake was blunted in Dahl S rats,16,19 indicating that the abnormal responses of the above protective genes may be due to a defect of HIF-1α in the Renal Medulla and that impairment in HIF-1α–mediated gene activation in the Renal Medulla may be responsible for salt-sensitive hypertension in Dahl S rats. Indeed, correction of HIF-1α deficiency in the Renal Medulla increased the expression of antihypertensive genes in the Renal Medulla, enhanced the urinary sodium excretion, reduced sodium retention, and consequently, attenuated salt-sensitive hypertension in Dahl S rats.19 Furthermore, it has been demonstrated that HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1α, is the most abundant isoform of PHDs in the kidneys20,21 and is highly expressed in the Renal Medulla.16,20,21 We have shown that high salt intake suppresses the expression of PHD2 in the Renal Medulla and that this high salt–induced inhibition of PHD2 is an upstream signal that increases HIF-1α–mediated gene expression in the Renal Medulla in response to high-salt challenge.16 Notably, the high salt–induced inhibition in PHD2 in the Renal Medulla is also defective in Dahl S rats.16 This study sought to test the hypothesis that deficiency in PHD2/HIF-1α–mediated molecular adaptation in response to high salt intake in the Renal Medulla may be the pathogenic mechanism responsible for salt-sensitive hypertension and that silencing the PHD2 gene to increase the levels of HIF-1α and its target genes in the Renal Medulla enhances the sodium excretion and attenuates salt-sensitive hypertension in Dahl S rats. We first transfected PHD2 short hairpin RNA (shRNA) plasmids into the Renal Medulla and then detected the pressure natriuresis, the Renal sodium excretion after sodium overload, and the arterial blood pressure after high-salt challenge in Dahl S rats. Our data showed that correction of the defect in PHD2 response to high salt intake attenuated salt-sensitive hypertension in Dahl S rats.
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Overexpression of HIF prolyl-hydoxylase-2 transgene in the Renal Medulla induced a salt sensitive hypertension.
Journal of cellular and molecular medicine, 2012Co-Authors: Qing Zhu, Wei-qing Han, Miao Liu, Zhengchao WangAbstract:Renal Medullary hypoxia-inducible factor (HIF)-1α and its target genes, such as haem oxygenase and nitric oxide synthase, have been indicated to play an important role in the regulation of sodium excretion and blood pressure. HIF prolyl hydroxylase domain-containing proteins (PHDs) are major enzymes to promote the degradation of HIF-1α. We recently reported that high salt intake suppressed the Renal Medullary PHD2 expression and thereby activated HIF-1α-mediated gene regulation in the Renal Medulla in response to high salt. To further define the functional role of Renal Medullary PHD2 in the regulation of Renal adaptation to high salt intake and the longer term control of blood pressure, we transfected PHD2 expression plasmids into the Renal Medulla in uninephrectomized rats and determined its effects on pressure natriuresis, sodium excretion after salt overloading and the long-term control of arterial pressure after high salt challenge. It was shown that overexpression of PHD2 transgene increased PHD2 levels and decreased HIF-1α levels in the Renal Medulla, which blunted pressure natriuresis, attenuated sodium excretion, promoted sodium retention and produced salt sensitive hypertension after high salt challenge compared with rats treated with control plasmids. There was no blood pressure change in PHD2-treated rats that were maintained in low salt diet. These results suggested that Renal Medullary PHD2 is an important regulator in Renal adaptation to high salt intake and a deficiency in PHD2-mediated molecular adaptation in response to high salt intake in the Renal Medulla may represent a pathogenic mechanism producing salt sensitive hypertension.
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Abstract 35: Transplantation of Mesenchymal Stem Cells into the Renal Medulla Attenuated Salt-sensitive Hypertension in Dahl S Rat
Hypertension, 2012Co-Authors: Qing Zhu, Wei-qing HanAbstract:Transplantation of mesenchymal stem cells (MSCs) has been employed as a therapeutic strategy for many different diseases. We have recently shown that there is a stem cell dysfunction in the Renal Medulla that may contribute to the development of salt-sensitive hypertension in Dahl S rats. The present study tested the hypothesis that transplantation of MSCs into the Renal Medulla improves salt-sensitive hypertension in Dahl S rats. Rat adult MSCs were obtained from Texas A&M Health Science Center, ex-vivo expanded and infused (5 million cells) into the Renal Medulla in uninephrectomized Dahl S rats, which were then treated with low salt (LS, 0.4% NaCl) or high salt (HS, 8% NaCl) diet for 10 days. Results showed that the mRNA levels of stem cell markers CD133 and CD90 were increased by 60% and 70%, respectively, in the Renal Medulla in MSC-treated rats compared with control cell-treated rats. HS challenge increased mean arterial blood pressure in control cell-treated animals (from 113.9 ± 3.4 to 153.5 ± 4.8 mmHg), which was significantly attenuated in MSC-treated animals (from 114.1 ± 3.5 to 131.3 ± 2.5 mmHg). Meanwhile, ELISA analysis showed that the levels of pro-inflammatory cytokine interleukin-1β in the Renal Medulla were remarkably increased in HS-treated rats compared with LS-treated rats, which was blocked in MSC-treated rats (1.81 ± 0.18 ng/mg protein in LS group, 2.84 ± 0.57 in HS +control cell and 1.83 ± 0.35 in HS+MSC). Furthermore, immunostaining showed that the significant increase in immune cell (CD43+) infiltration into the Renal Medulla in HS control rats was reduced in HS+MSC rats. These results suggest that correction of stem cell dysfunction in the Renal Medulla attenuated inflammation in this kidney region after HS challenge and improved high salt-induced hypertension in Dahls S rats, which may serve as a therapeutic approach for salt-sensitive hypertension (supported by NIH grant HL89563 and HL106042)
Fan Zhang - One of the best experts on this subject based on the ideXlab platform.
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Silencing of HIF prolyl-hydroxylase 2 gene in the Renal Medulla attenuates salt-sensitive hypertension in Dahl S rats.
American journal of hypertension, 2013Co-Authors: Qing Zhu, Fan Zhang, Wei-qing Han, Zhengchao WangAbstract:Salt-sensitive hypertension accounts for 50% of hypertension cases1 and exhibits a much higher risk for development of organ damage than salt-resistant hypertension.2,3 The mechanism regulating salt sensitivity of blood pressure is not very clear. Renal Medullary function is well known to play a critical role in the regulation of sodium excretion and blood pressure, and it is known that dysfunction in the Renal Medulla is involved in salt-sensitive hypertension.4,5 We have recently shown that transcription factor hypoxia-inducible factor (HIF) 1α–mediated activation of antihypertensive genes in the Renal Medulla enhances the production of a variety of protective factors in the Renal Medulla, which promotes the excretion of extra sodium load and regulates the Renal adaptation to high salt intake.6 HIF-1α and many HIF-1α target genes, such as hemeoxygenase 1 (HO-1), cyclooxygenase 2 (COX-2), nitric oxide synthase 2 (NOS-2), and endothelin 1, are highly expressed in the Renal Medulla and significantly upregulated in response to high salt intake.7–13 The products of these HIF-1α target genes importantly participate in the regulation of blood flow and/or tubular activity in the Renal Medulla and play critical roles in sodium balance and long-term control of arterial blood pressure as well as salt sensitivity of blood pressure.7,8,11–15 We have demonstrated that high salt diet upregulates HIF-1α levels in the Renal Medulla6,16 and that blockade of HIF-1α function to inhibit the expression of its target genes in the Renal Medulla induces sodium retention after high-salt challenge, producing a salt-sensitive hypertension.6 These results suggest that HIF-1α–mediated gene activation in the Renal Medulla represents an important molecular adaptive mechanism to maintain sodium balance in response to high salt intake. Interestingly, it has been shown that the above protective genes regulated by HIF-1α are defective in Dahl salt-sensitive hypertensive (Dahl S) rats12,13,16–18 and that the deficiencies of these HIF-1α target genes in the Renal Medulla are considered to be responsible for the development of hypertension in this animal model.12,13,17 We recently showed that upregulation of Renal Medullary HIF-1α levels in response to high salt intake was blunted in Dahl S rats,16,19 indicating that the abnormal responses of the above protective genes may be due to a defect of HIF-1α in the Renal Medulla and that impairment in HIF-1α–mediated gene activation in the Renal Medulla may be responsible for salt-sensitive hypertension in Dahl S rats. Indeed, correction of HIF-1α deficiency in the Renal Medulla increased the expression of antihypertensive genes in the Renal Medulla, enhanced the urinary sodium excretion, reduced sodium retention, and consequently, attenuated salt-sensitive hypertension in Dahl S rats.19 Furthermore, it has been demonstrated that HIF prolyl-hydroxylase 2 (PHD2), an enzyme that promotes the degradation of HIF-1α, is the most abundant isoform of PHDs in the kidneys20,21 and is highly expressed in the Renal Medulla.16,20,21 We have shown that high salt intake suppresses the expression of PHD2 in the Renal Medulla and that this high salt–induced inhibition of PHD2 is an upstream signal that increases HIF-1α–mediated gene expression in the Renal Medulla in response to high-salt challenge.16 Notably, the high salt–induced inhibition in PHD2 in the Renal Medulla is also defective in Dahl S rats.16 This study sought to test the hypothesis that deficiency in PHD2/HIF-1α–mediated molecular adaptation in response to high salt intake in the Renal Medulla may be the pathogenic mechanism responsible for salt-sensitive hypertension and that silencing the PHD2 gene to increase the levels of HIF-1α and its target genes in the Renal Medulla enhances the sodium excretion and attenuates salt-sensitive hypertension in Dahl S rats. We first transfected PHD2 short hairpin RNA (shRNA) plasmids into the Renal Medulla and then detected the pressure natriuresis, the Renal sodium excretion after sodium overload, and the arterial blood pressure after high-salt challenge in Dahl S rats. Our data showed that correction of the defect in PHD2 response to high salt intake attenuated salt-sensitive hypertension in Dahl S rats.
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Overexpression of HIF-1α transgene in the Renal Medulla attenuated salt sensitive hypertension in Dahl S rats
Biochimica et biophysica acta, 2012Co-Authors: Qing Zhu, Zhengchao Wang, Min Xia, Fan ZhangAbstract:Hypoxia inducible factor (HIF)-1α-mediated gene activation in the Renal Medulla in response to high salt intake plays an important role in the control of salt sensitivity of blood pressure. High salt-induced activation of HIF-1α in the Renal Medulla is blunted in Dahl S rats. The present study determined whether the impairment of the Renal Medullary HIF-1α pathway was responsible for salt sensitive hypertension in Dahl S rats. Renal Medullary HIF-1α levels were induced by either transfection of HIF-1α expression plasmid or chronic infusion of CoCl2 into the Renal Medulla, which was accompanied by increased expressions of anti-hypertensive genes, cyclooxygenase-2 and heme oxygenase-1. Overexpression of HIF-1α transgenes in the Renal Medulla enhanced the pressure natriuresis, promoted the sodium excretion and reduced sodium retention after salt overload. As a result, hypertension induced by 2-week high salt was significantly attenuated in rats treated with HIF-1α plasmid or CoCl2. These results suggest that an abnormal HIF-1α in the Renal Medulla may represent a novel mechanism mediating salt-sensitive hypertension in Dahl S rats and that induction of HIF-1α levels in the Renal Medulla could be a therapeutic approach for the treatment of salt-sensitive hypertension.
Min Xia - One of the best experts on this subject based on the ideXlab platform.
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Production and Actions of the Anandamide Metabolite Prostamide E2 in the Renal Medulla
The Journal of pharmacology and experimental therapeutics, 2012Co-Authors: Joseph K. Ritter, Min Xia, Justin L. Poklis, Aron H. Lichtman, Rehab A. Abdullah, William L. DeweyAbstract:Medullipin has been proposed to be an antihypertensive lipid hormone released from the Renal Medulla in response to increased arterial pressure and Renal Medullary blood flow. Because anandamide (AEA) possesses characteristics of this purported hormone, the present study tested the hypothesis that AEA or one of its metabolites represents medullipin. AEA was demonstrated to be enriched in the kidney Medulla compared with cortex. Western blotting and enzymatic analyses of Renal cortical and Medullary microsomes revealed opposite patterns of enrichment of two AEA-metabolizing enzymes, with fatty acid amide hydrolase higher in the Renal cortex and cyclooxygenase-2 (COX-2) higher in the Renal Medulla. In COX-2 reactions with Renal Medullary microsomes, prostamide E2, the ethanolamide of prostaglandin E2, was the major product detected. IntraMedullarily infused AEA dose-dependently increased urine volume and sodium and potassium excretion (15–60 nmol/kg/min) but had little effect on mean arterial pressure (MAP). The Renal excretory effects of AEA were blocked by intravenous infusion of celecoxib (0.1 μg/kg/min), a selective COX-2 inhibitor, suggesting the involvement of a prostamide intermediate. Plasma kinetic analysis revealed longer elimination half-lives for AEA and prostamide E2 compared with prostaglandin E2. Intravenous prostamide E2 reduced MAP and increased Renal blood flow (RBF), actions opposite to those of angiotensin II. Coinfusion of prostamide E2 inhibited angiotensin II effects on MAP and RBF. These results suggest that AEA and/or its prostamide metabolites in the Renal Medulla may represent medullipin and function as a regulator of body fluid and MAP.
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Overexpression of HIF-1α transgene in the Renal Medulla attenuated salt sensitive hypertension in Dahl S rats
Biochimica et biophysica acta, 2012Co-Authors: Qing Zhu, Zhengchao Wang, Min Xia, Fan ZhangAbstract:Hypoxia inducible factor (HIF)-1α-mediated gene activation in the Renal Medulla in response to high salt intake plays an important role in the control of salt sensitivity of blood pressure. High salt-induced activation of HIF-1α in the Renal Medulla is blunted in Dahl S rats. The present study determined whether the impairment of the Renal Medullary HIF-1α pathway was responsible for salt sensitive hypertension in Dahl S rats. Renal Medullary HIF-1α levels were induced by either transfection of HIF-1α expression plasmid or chronic infusion of CoCl2 into the Renal Medulla, which was accompanied by increased expressions of anti-hypertensive genes, cyclooxygenase-2 and heme oxygenase-1. Overexpression of HIF-1α transgenes in the Renal Medulla enhanced the pressure natriuresis, promoted the sodium excretion and reduced sodium retention after salt overload. As a result, hypertension induced by 2-week high salt was significantly attenuated in rats treated with HIF-1α plasmid or CoCl2. These results suggest that an abnormal HIF-1α in the Renal Medulla may represent a novel mechanism mediating salt-sensitive hypertension in Dahl S rats and that induction of HIF-1α levels in the Renal Medulla could be a therapeutic approach for the treatment of salt-sensitive hypertension.
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A novel lipid natriuretic factor in the Renal Medulla: sphingosine-1-phosphate
American journal of physiology. Renal physiology, 2011Co-Authors: Qing Zhu, Min Xia, Zhengchao WangAbstract:Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by phosphorylation of sphingosine. S1P has been indicated to play a significant role in the cardiovascular system. It has been shown that the enzymes for S1P metabolism are expressed in the kidneys. The present study characterized the expression of S1P receptors in the kidneys and determined the role of S1P in the control of Renal hemodynamics and sodium excretion. Real-time RT-PCR analyses showed that S1P receptors S1P1, S1P2, and S1P3 were most abundantly expressed in the Renal Medulla. Immunohistochemistry revealed that all three types of S1P receptors were mainly located in collecting ducts. IntraMedullary infusion of FTY720, an S1P agonist, produced a dramatic increase in sodium excretion by twofold and a small but significant increase in Medullary blood flow (16%). Administration of W146, an S1P1 antagonist, into the Renal Medulla blocked the effect of FTY720 and decreased the sodium excretion by 37% when infused alone. The antagonists of S1P2 and S1P3 had no effect. FTY720 produced additive natriuretic effects in combination with different sodium transporter inhibitors except amiloride, an epithelial sodium channel blocker. In the presence of nitric oxide synthase inhibitor l-NAME, FTY720 still increased sodium excretion. These data suggest that S1P produces natriuretic effects via activation of S1P1 in the Renal Medulla and this natriuretic effect may be through inhibition of epithelial sodium channel, which is nitric oxide independent. It is concluded that S1P is a novel diuretic factor in the Renal Medulla and may be an important regulator of sodium homeostasis.
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Hypoxia-Inducible Factor Prolyl-Hydroxylase 2 Senses High-Salt Intake to Increase Hypoxia Inducible Factor 1α Levels in the Renal Medulla
Hypertension (Dallas Tex. : 1979), 2010Co-Authors: Zhengchao Wang, Qing Zhu, Min Xia, Shante J. HintonAbstract:High salt induces the expression of transcription factor hypoxia-inducible factor (HIF) 1α and its target genes in the Renal Medulla, which is an important Renal adaptive mechanism to high-salt intake. HIF prolyl-hydroxylase domain-containing proteins (PHDs) have been identified as major enzymes to promote the degradation of HIF-1α. PHD2 is the predominant isoform of PHDs in the kidney and is primarily expressed in the Renal Medulla. The present study tested the hypothesis that PHD2 responds to high salt and mediates high-salt–induced increase in HIF-1α levels in the Renal Medulla. In normotensive rats, high-salt intake (4% NaCl, 10 days) significantly inhibited PHD2 expressions and enzyme activities in the Renal Medulla. Renal Medullary overexpression of the PHD2 transgene significantly decreased HIF-1α levels. PHD2 transgene also blocked high-salt–induced activation of HIF-1α target genes heme oxygenase 1 and NO synthase 2 in the Renal Medulla. In Dahl salt-sensitive hypertensive rats, however, high-salt intake did not inhibit the expression and activities of PHD2 in the Renal Medulla. Correspondingly, Renal Medullary HIF-1α levels were not upregulated by high-salt intake in these rats. After transfection of PHD2 small hairpin RNA, HIF-1α and its target genes were significantly upregulated by high-salt intake in Dahl salt-sensitive rats. Overexpression of PHD2 transgene in the Renal Medulla impaired Renal sodium excretion after salt loading. These data suggest that high-salt intake inhibits PHD2 in the Renal Medulla, thereby upregulating the HIF-1α expression. The lack of PHD-mediated response to high salt may represent a pathogenic mechanism producing salt-sensitive hypertension.
