Role of homocysteine metabolism, endothelial function and microvascular rarefaction on renal disease severity and progression in ADPKD

同型半胱氨酸代谢、内皮功能和微血管稀疏对 ADPKD 肾脏疾病严重程度和进展的作用

• 批准号: 10598067
• 负责人: Maria V Irazabal
• 金额: $ 61.83万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598067
• 关键词: Address; Adult; Amino Acids; Animal Model; Animals; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Autosomal Dominant Polycystic Kidney; Basic Science; Betaine; Bilateral; Biological; Biological Markers; Blood Pressure; Blood Vessels; Blood capillaries; Clinical Trials; Cyst; Cystic kidney; Data; Development; Disease; Disease Progression; Down-Regulation; Early identification; Early treatment; Endothelial Cells; Endothelium; Enzymes; Epithelial Cells; Evaluation; Functional disorder; Healthcare Systems; Histological Techniques; Homocysteine; Hypertension; Imaging Techniques; In Vitro; Injury; Intervention; Kidney; Kidney Diseases; Kidney Failure; Longitudinal Studies; Metabolism; Modeling; Modification; Monitor; Mus; NADPH Oxidase; Nitric Oxide; Nitric Oxide Synthase; Outcome; Oxidation-Reduction; PKD2 gene; Pathology; Patients; Peripheral; Phenotype; Plasma; Play; Rattus; Regulation; Renal function; Reporting; Role; Severities; Severity of illness; Sulfhydryl Compounds; Techniques; Testing; Therapeutic Intervention; Tubular formation; Up-Regulation; Urine; Vascular remodeling; Vasodilation; arterial tonometry; blood pressure elevation; cost; endothelial dysfunction; in vivo; indexing; kidney preservation; new therapeutic target; normotensive; novel marker; pharmacologic; pre-clinical; preservation; prognostic value; renal epithelium; specific biomarkers; targeted biomarker; targeted treatment; treatment effect; treatment response; vascular abnormality; vasoconstriction

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating systemic disorder characterized by progressive development and enlargement of bilateral renal cysts leading to renal failure. Disease severity and progression vary widely among patients. Large phenotypic variability, incomplete understanding of underlying mechanisms, and lack of satisfactory biomarkers challenge the identification, implementation and evaluation of potential therapies. In ADPKD, endothelial dysfunction (ED), characterized by an imbalance between vasodilating (particularly nitric oxide, NO) and vasoconstricting substances, develops early on and correlates with renal disease severity. We propose that preservation of endothelial function will ameliorate renal disease severity and progression. Increased homocysteine has been reported in patients with ADPKD even in those with preserved kidney function. Homocysteine decreases NO availability. However, the mechanisms underlying increased homocysteine in ADPKD are not known. Elevations in homocysteine reflect changes in its metabolism, which can be modulated by NADPH oxidase 4 (NOX4). In line with this, we found upregulation of NOX4, and increased homocysteine, in Pkd1RC/RC mice with early disease. Pharmacologic reduction of NOX4 restored homocysteine metabolism and reduced cystic burden. Betaine, known to decrease plasma homocysteine, preserved capillary index, and reduced cystic burden of Pkd1RC/RC mice. Systemic endothelial function inversely correlated with urine NOX4, plasma homocysteine and renal disease severity by kidney volume in young normotensive patients with ADPKD. However, whether upregulation of NOX4 redirect homocysteine metabolism leading to decreased NO availability and ED, and the extent to which ED and microvascular abnormalities contribute to renal disease severity remain unknown. Similarly, whether markers of ROS, endothelial function and injury, or levels of homocysteine can predict disease severity and progression in patients is not known. Our central hypothesis is that early upregulation of NOX4 redirects homocysteine metabolism leading to its accumulation, which in turn decreases NO availability leading to ED and microvascular damage, which contributes to ADPKD severity and progression. Three specific aims will be pursued: Aim 1: will test whether early upregulation in NOX4 redirects homocysteine metabolism leading to its accumulation in ADPKD. Aim 2: will test whether accumulation of homocysteine decreases NO availability leading to ED, and whether ED leads to microvascular damage and contributes to disease severity and progression. Aim 3: will determine the prognostic value of markers of ROS, endothelial function and injury, and levels of homocysteine to assess disease severity and progression in patients with early ADPKD. Successful studies will reveal the contribution of microvascular damage to the severity and progression of ADPKD, and will provide critical biological, preclinical evidence, and rationale to justify clinical trials targeting homocysteine metabolism for this disease.

常染色体显性多囊肾病（ADPKD）是一种毁灭性的全身性疾病