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: 10176910
• 负责人: Maria V Irazabal
• 金额: $ 61.61万
• 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/10176910
• 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; Lead; Longitudinal Studies; Metabolism; Modeling; Modification; Monitor; Mus; NADPH Oxidase; Nitric Oxide; Nitric Oxide Synthase; Outcome; Oxidation-Reduction; Pathology; Patients; Peripheral; Pharmacology; Phenotype; Plasma; Play; Rattus; Regulation; Renal function; Reporting; Role; Severities; Severity of illness; Sulfhydryl Compounds; Techniques; Testing; Therapeutic Intervention; Tubular formation; Up-Regulation; Urine; arterial tonometry; cost; endothelial dysfunction; in vivo; indexing; kidney preservation; new therapeutic target; normotensive; novel marker; pre-clinical; preservation; prognostic value; renal epithelium; response; specific biomarkers; targeted biomarker; targeted treatment; treatment effect

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脏疾病（ADPKD）是一种毁灭性的全身性疾病 以逐步发展和双侧肾囊肿的扩大导致肾衰竭的特征。 疾病的严重程度和进展差异很大。大型表型变异性，不完整 了解潜在机制，缺乏令人满意的生物标志物挑战识别， 潜在疗法的实施和评估。在ADPKD中，内皮功能障碍（ED），表征 通过血管散发（尤其是一氧化氮，NO）和血管收缩物质之间的不平衡 早期，与肾脏疾病的严重程度相关。我们建议保存内皮功能 改善肾脏疾病的严重程度和进展。据报道，同型半胱氨酸的增加患者 ADPKD即使在保留肾功能的人也是如此。同型半胱氨酸降低没有可用性。但是， ADPKD中同型半胱氨酸增加的机制尚不清楚。同型半胱氨酸的高程反射 其代谢的变化可以通过NADPH氧化酶4（NOX4）调节。因此，我们发现 在患有早期疾病的PKD1RC/RC小鼠中，NOX4的上调和同型半胱氨酸的上调。药理学 减少NOX4恢复了同型半胱氨酸代谢并减轻了囊性负担。甜菜碱，已知会减少 血浆同型半胱氨酸，保留的毛细血管指数和PKD1RC/RC小鼠的囊性负担减轻。系统性 内皮功能与尿液NOX4，血浆同型半胱氨酸和肾脏疾病严重程度成反比 ADPKD年轻患者的肾脏体积。但是，是否上调NOX4重定向 同型半胱氨酸代谢导致没有可用性和ED的降低，以及ED和ED的程度 微血管异常导致肾脏疾病严重程度尚不清楚。同样，是否标记 ROS，内皮功能和损伤或同型半胱氨酸水平可以预测疾病的严重程度和进展 在患者中尚不清楚。我们的中心假设是NOX4重定向的早期上调 同型半胱氨酸代谢导致其累积 ED和微血管损伤有助于ADPKD的严重程度和进展。三个具体 将追求目标：目标1：将测试NOX4中早期上调是否重定向同型半胱氨酸代谢 导致其积累在ADPKD中。 AIM 2：将测试同型半胱氨酸的积累是否降低NO 导致ED的可用性以及ED是否导致微血管损伤并导致疾病严重程度 和进展。 AIM 3：将确定ROS标记，内皮功能和伤害的预后价值， 以及评估早期ADPKD患者疾病严重程度和进展的同型半胱氨酸的水平。 成功的研究将揭示微血管损伤对严重程度和进展的贡献 ADPKD，并将提供关键的生物学，临床前证据和理由，以证明针对临床试验的合理性 该疾病的同型半胱氨酸代谢。