Transcriptional regulation of renal dopamine D1 receptors in hypertension during

高血压期间肾脏多巴胺 D1 受体的转录调控

• 批准号: 8881163
• 负责人: Mustafa F. Lokhandwala
• 金额: $ 32.73万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881163
• 关键词: Agonist; Animals; Antioxidants; Binding; Blood Pressure; Buthionine Sulfoximine; Cardiovascular Diseases; Cell Line; Cells; Chemicals; Chronic Disease; Clinical Trials; Data; Development; Diabetes Mellitus; Diet; Disease; Dopamine; Dopamine D1 Receptor; Effectiveness; Environmental Risk Factor; Epithelial Cells; Excretory function; Exhibits; Failure; Food; Functional disorder; Genes; Genetic; Glutathione; HK2 gene; Health; Health Benefit; Human; Hypertension; Hypotension; Kidney; Knock-out; Knockout Mice; Lead; Link; Malignant Neoplasms; Mediating; Menopausal Symptom; Monitor; Morbidity - disease rate; Mus; Na(+)-K(+)-Exchanging ATPase; Natriuresis; Nutraceutical; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phase; Plants; Plasmids; Play; Population; Predisposition; Property; Proteins; Proximal Kidney Tubules; Public Health; Reactive Oxygen Species; Receptor Activation; Receptor Down-Regulation; Receptor Gene; Recommendation; Regulation; Renal function; Reporter; Reporting; Research; Resveratrol; Risk Factors; Role; SKF38393; Severities; Signal Pathway; Signal Transduction; Sodium; Sulforaphane; System; Telemetry; Testing; Therapeutic; Transcription Factor AP-1; Transcriptional Activation; Transcriptional Regulation; Translating; Tubular formation; Up-Regulation; Wild Type Mouse; Xanthine Oxidase; Xanthines; activating transcription factor; base; blood pressure reduction; blood pressure regulation; diabetic patient; evidence base; improved; inhibitor/antagonist; kidney cell; mortality; novel; novel therapeutic intervention; novel therapeutics; nuclear factor-erythroid 2; polyphenol; promoter; protective effect; receptor expression; receptor function; research study; transcription factor

DESCRIPTION (provided by applicant): Redox sensitive transcription factors are pivotal in maintaining the normal oxidative milieu of cells. While an imbalance in redox status is implicated in hypertension, the link between this phenomenon and hypertension is not clear. In addition, it has been shown that many bioactive compounds, extranutritional constituents (nutraceuticals) that typically occur in small quantities in foods, have antioxidant properties and lower blood pressure, the exact mechanism for these beneficial effects is unclear. We, and others, have reported that renal dopamine via activation of D1 receptor (D1R) plays a major role in regulation of sodium homeostasis and blood pressure (BP). Renal D1R function is down-regulated in chronic diseases, especially in oxidative stress related hypertension and diabetes. Therefore, the identification of cellular molecules which contributes to D1R dysfunction as well as the mechanism by which dietary compounds can preserve renal D1R function will provide a novel therapeutic approach to mitigate hypertension. Transcription factors such as AP1 and SP3 play an important role in oxidative stress related pathophysiological conditions. Conversely, redox sensitive transcription factor Nrf2 activates a highly regulated defense system against oxidative stress which involves transcriptional activation of phase II defense and antioxidant genes. Our preliminary studies showed that mice treated with L-buthionine-sulfoximine (BSO), a glutathione synthesis pathway inhibitor exhibited oxidative stress, high BP, renal proximal tubular D1R dysfunction and up-regulation of AP1 and SP3. These phenomena were exaggerated in BSO-treated renal proximal tubule specific Nrf2 knockout mice. More importantly, sulforaphane (a polyphenol antioxidant) activated Nrf2, reduced oxidative stress, normalized AP1 and SP3 activation, preserved DIR function and lowered BP in BSO-treated wild type mice but failed to normalize renal D1R function or reduce BP in Nrf2 knockout mice. Further experiments in human kidney cells (a proximal tubular epithelial cell line) also indicated that: 1) BSO via AP1 activated SP3 which in turn transcriptionally down-regulated D1R expression and 2) sulforaphane, via Nrf2 activation, abolished BSO-induced AP1 and SP3 activation and D1R dysfunction. These findings led us to hypothesize that: 1) oxidative stress via AP1-SP3 pathway down-regulates D1R expression and function which leads to decrease in sodium excretion and hypertension and 2) antioxidants via Nrf2 activation reduce oxidative stress and normalize AP1-SP3 signaling and D1R function which reduces BP. Therefore, it is likely that polyphenols, such as sulforaphane and resveratrol, via activation of Nrf2 signaling would provide a novel mechanism to protect D1R function and mitigate hypertension during oxidative stress. These studies will have significant impact on understanding the mechanisms for potential public health benefits of antioxidants as recent studies in humans have shown that polyphenols and direct Nrf2 activators can reduce BP and improve kidney function in CKD and type 2 diabetic patients.

DESCRIPTION (provided by applicant): Redox sensitive transcription factors are pivotal in maintaining the normal oxidative milieu of cells. While an imbalance in redox status is implicated in hypertension, the link between this phenomenon and hypertension is not clear. In addition, it has been shown that many bioactive compounds, extranutritional constituents (nutraceuticals) that typically occur in small quantities in foods, have antioxidant properties and lower blood pressure, the exact mechanism for these beneficial effects is unclear. We, and others, have reported that renal dopamine via activation of D1 receptor (D1R) plays a major role in regulation of sodium homeostasis and blood pressure (BP). Renal D1R function is down-regulated in chronic diseases, especially in oxidative stress related hypertension and diabetes. Therefore, the identification of cellular molecules which contributes to D1R dysfunction as well as the mechanism by which dietary compounds can preserve renal D1R function will provide a novel therapeutic approach to mitigate hypertension. Transcription factors such as AP1 and SP3 play an important role in oxidative stress related pathophysiological conditions. Conversely, redox sensitive transcription factor Nrf2 activates a highly regulated defense system against oxidative stress which involves transcriptional activation of phase II defense and antioxidant genes. Our preliminary studies showed that mice treated with L-buthionine-sulfoximine (BSO), a glutathione synthesis pathway inhibitor exhibited oxidative stress, high BP, renal proximal tubular D1R dysfunction and up-regulation of AP1 and SP3. These phenomena were exaggerated in BSO-treated renal proximal tubule specific Nrf2 knockout mice. More importantly, sulforaphane (a polyphenol antioxidant) activated Nrf2, reduced oxidative stress, normalized AP1 and SP3 activation, preserved DIR function and lowered BP in BSO-treated wild type mice but failed to normalize renal D1R function or reduce BP in Nrf2 knockout mice. Further experiments in human kidney cells (a proximal tubular epithelial cell line) also indicated that: 1) BSO via AP1 activated SP3 which in turn transcriptionally down-regulated D1R expression and 2) sulforaphane, via Nrf2 activation, abolished BSO-induced AP1 and SP3 activation and D1R dysfunction. These findings led us to hypothesize that: 1) oxidative stress via AP1-SP3 pathway down-regulates D1R expression and function which leads to decrease in sodium excretion and hypertension and 2) antioxidants via Nrf2 activation reduce oxidative stress and normalize AP1-SP3 signaling and D1R function which reduces BP. Therefore, it is likely that polyphenols, such as sulforaphane and resveratrol, via activation of Nrf2 signaling would provide a novel mechanism to protect D1R function and mitigate hypertension during oxidative stress. These studies will have significant impact on understanding the mechanisms for potential public health benefits of antioxidants as recent studies in humans have shown that polyphenols and direct Nrf2 activators can reduce BP and improve kidney function in CKD and type 2 diabetic patients.