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: 10398925
• 负责人: Maria V Irazabal
• 金额: $ 62.18万
• 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/10398925
• 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; blood pressure elevation; cost; endothelial dysfunction; in vivo; indexing; kidney preservation; new therapeutic target; normotensive; novel marker; pre-clinical; preservation; prognostic value; renal epithelium; specific biomarkers; targeted biomarker; targeted treatment; treatment effect; treatment response

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) 是一种毁灭性的系统性疾病 其特征是双侧肾囊肿进行性发展和增大，导致肾功能衰竭。 患者之间的疾病严重程度和进展差异很大。表型变异大，不完整 对潜在机制的理解，以及缺乏令人满意的生物标志物对识别提出了挑战， 潜在疗法的实施和评估。在 ADPKD 中，内皮功能障碍 (ED) 的特点是 由于血管舒张物质（特别是一氧化氮，NO）和血管收缩物质之间的不平衡， 早期并与肾脏疾病的严重程度相关。我们建议，内皮功能的保存将 改善肾脏疾病的严重程度和进展。据报道，患有以下疾病的患者体内同型半胱氨酸升高 ADPKD 甚至存在于肾功能保留的患者中。同型半胱氨酸会降低 NO 的可用性。然而， ADPKD 中同型半胱氨酸增加的机制尚不清楚。同型半胱氨酸的升高反映了 其代谢发生变化，可由 NADPH 氧化酶 4 (NOX4) 调节。与此相符，我们发现 在患有早期疾病的 Pkd1RC/RC 小鼠中，NOX4 上调并增加同型半胱氨酸。药理作用 NOX4 的减少恢复了同型半胱氨酸代谢并减少了囊肿负担。甜菜碱，已知会减少 Pkd1RC/RC 小鼠的血浆同型半胱氨酸、保留的毛细血管指数和减少的囊肿负担。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呈负相关 年轻血压正常的 ADPKD 患者的肾脏体积。然而，NOX4 重定向是否上调 同型半胱氨酸代谢导致 NO 可用性和 ED 降低，以及 ED 和 ED 的程度 微血管异常对肾脏疾病严重程度的影响仍不清楚。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 患者中的情况尚不清楚。我们的中心假设是 NOX4 的早期上调重定向 同型半胱氨酸代谢导致其积累，进而降低 NO 的可用性，导致 ED 和微血管损伤，从而导致 ADPKD 的严重程度和进展。三具体 将追求的目标： 目标 1：将测试 NOX4 的早期上调是否会重定向同型半胱氨酸代谢 导致其在 ADPKD 中积累。目标 2：测试同型半胱氨酸的积累是否会降低 NO 导致 ED 的可用性，以及 ED 是否会导致微血管损伤并导致疾病严重程度 和进展。目标 3：将确定 ROS、内皮功能和损伤标志物的预后价值， 和同型半胱氨酸水平，以评估早期 ADPKD 患者的疾病严重程度和进展。 成功的研究将揭示微血管损伤对疾病严重程度和进展的影响 ADPKD，并将提供关键的生物学、临床前证据和基本原理来证明针对目标的临床试验的合理性 本病的同型半胱氨酸代谢。