NOX4-associated oxidative stress mediates vascular and kidney impairment in the low birth weight adult

NOX4相关的氧化应激介导低出生体重成人的血管和肾脏损伤

• 批准号: 9916890
• 负责人: Brian Blake Ratliff
• 金额: $ 41万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916890
• 关键词: Ablation; Adult; Aminolevulinic Acid; Animals; Automobile Driving; Biological Availability; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic Kidney Failure; Cultured Cells; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Female; Functional disorder; Gender; Generations; Genetic; HMGB1 gene; Human; Hypertension; Hypertrophy; Impairment; Inflammation; Interleukin-1 beta; Intervention; Kidney; Kidney Diseases; Lead; Low Birth Weight Infant; Measurement; Mediating; Medicine; Membrane; Metabolic; Mitochondria; Mitochondrial Matrix; Modeling; Mus; NADP; NADPH Oxidase; Neonatal; Nitric Oxide; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Pathologic; Pathology; Pathway interactions; Perfusion; Population; Process; Regulation; Renal Blood Flow; Renal Hypertension; Renal function; Respiration; Role; Signal Transduction; Smooth Muscle Myocytes; Soluble Guanylate Cyclase; Sulfhydryl Compounds; Superoxides; System; TLR4 gene; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Vascular Diseases; driving force; endothelial dysfunction; ethyl pyruvate; experience; experimental study; heme biosynthesis; inhibitor/antagonist; iron metabolism; kidney dysfunction; kidney fibrosis; kidney vascular structure; male; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; offspring; oxidation; pregnant; prevent; sensor; tempol; vasoconstriction

PROJECT ABSTRACT Recent advances in neonatal medicine have increased the population of low birth weight (LBW) babies that are incredibly susceptible for development of hypertension, cardiovascular disease and chronic kidney disease for unknown reasons as they mature through adulthood. Using an undernourished pregnant mouse model to generate LBW offspring that develop pathologies similar to those in LBW humans, the proposed studies will investigate the association of vascular and kidney disease in the LBW adult with systems regulated by oxidative stress. The study will also examine new potential therapeutic strategies that target vascular oxidant- regulated mechanisms to treat hypertension and renal dysfunction. Our current studies have provided evidence for NADPH oxidase-4 (NOX4) driven increases in superoxide-mediated endothelial nitric oxide dysfunction, thiol oxidation-mediated release of HMGB1 (which potentially activates TLR4) and IL-1β promoted inflammation as potential driving factors in the disease progression that the LBW adult experiences. Studies in Aim 1 will examine the consequences of LBW in Nox4 deficient mice and in LBW mice treated with agents that inhibit NOX4, scavenge superoxide (including superoxide in the mitochondrial matrix), stabilize cytosolic NADPH redox, and promote heme biosynthesis to define their impact on vascular dysfunction, impairment of renal perfusion and hypertension development. Measurements of a) redox and metabolic indicators or signaling mechanisms related to these approaches, b) alterations in vascular function, and c) alterations in tissue mitochondrial respiration and function will be made to help define driving forces in the progression of vascular and renal dysfunction that is observed. Using mice deficient in TLR4, and animals treated with inhibitors of HMGB1 release, TLR4 and IL-1β, studies in Aim 2 will focus on defining the role that the redox sensor HMGB1 has in causing inflammation, vascular rarefaction, renal fibrosis and glomerular hypertrophy associated with hypertension and kidney disease. Supporting mechanisms for the HMGB1-TLR4 activation processes will be defined in cells cultured from control and LBW animals. Studies in this aim will examine the role of TLR4 in the actions of oxidized forms of HMGB1, and the impact of TLR4 activation on endothelial cell mitochondrial dysfunction and release of IL-1β. The approaches and measurements made in Aim 1 will also be used to document the impact of the interventions in Aim 2 on relationships between redox regulatory processes and aspects of disease progression. It is hypothesized that the redox changes in HMGB1 (identified by mass spectral analyses) can potentially be modulated by the therapies employed in ways that could help define the HMGB1 redox forms that are the most pathologically active. It is anticipated that the studies proposed will document and define the driving factors that promote the progression of hypertension, cardiovascular and chronic kidney disease in LBW adults, in addition to identifying novel therapeutic approaches that target the systems that drive such disease progression.

项目摘要