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

常染色体显性遗传性多囊肾病（ADPKD）是一种严重的系统性疾病 以双侧肾囊肿的进行性发展和扩大为特征，导致肾衰竭。 疾病的严重程度和进展在患者之间差异很大。表型变异大，不完全 对潜在机制的理解，以及缺乏令人满意的生物标志物对鉴定提出了挑战， 实施和评估潜在的治疗方法。在ADPKD中，内皮功能障碍（艾德），其特征在于 由于血管扩张物质（特别是一氧化氮，NO）和血管收缩物质之间的不平衡，导致 与肾脏疾病的严重程度相关。我们认为，保护内皮功能将 改善肾脏疾病的严重程度和进展。据报道，高半胱氨酸水平升高的患者 ADPKD即使在那些保留肾功能的人中。同型半胱氨酸降低NO可用性。但 ADPKD中高半胱氨酸增加的潜在机制尚不清楚。同型半胱氨酸的升高反映了 其代谢的变化，这可以通过NADPH氧化酶4（NOX 4）调节。与此同时，我们发现 在患有早期疾病的Pkd 1 RC/RC小鼠中，NOX 4上调，同型半胱氨酸增加。药理学 NOX 4的减少恢复了同型半胱氨酸代谢并降低了囊性负荷。甜菜碱，已知减少 血浆同型半胱氨酸，保留毛细血管指数，并减少囊性负担的Pkd 1 RC/RC小鼠。系统性 内皮功能与尿NOX 4、血浆同型半胱氨酸和肾脏疾病严重程度呈负相关， 血压正常的年轻ADPKD患者的肾脏体积然而，是否上调NOX 4重定向 同型半胱氨酸代谢导致NO可用性和艾德降低，以及艾德和 微血管异常导致肾脏疾病的严重程度仍然未知。同样，无论标记 ROS、内皮功能和损伤的变化或同型半胱氨酸水平可以预测疾病的严重程度和进展 患者的情况尚不清楚。我们的中心假设是，早期上调的NOX 4重定向 同型半胱氨酸代谢导致其积累，这反过来又降低了NO的可用性， 艾德和微血管损伤，这有助于ADPKD的严重性和进展。三个具体 目标1：将测试NOX 4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：将测试高半胱氨酸的积累是否会减少NO 导致艾德的可用性，以及艾德是否导致微血管损伤并导致疾病严重程度 和进步。目的3：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来评估早期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肿瘤严重程度和进展的影响。 ADPKD，并将提供关键的生物学、临床前证据和理由，以证明临床试验靶向的合理性 同型半胱氨酸代谢的影响

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.