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)是一种破坏性的系统性疾病 以双侧肾囊肿逐渐发展和增大为特征，导致肾功能衰竭。 疾病的严重程度和进展在患者之间差别很大。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记物，对鉴定构成了挑战， 潜在疗法的实施和评估。在ADPKD中，以内皮功能障碍(ED)为特征 由于血管扩张(尤其是一氧化氮，NO)和血管收缩物质之间的失衡， 并与肾脏疾病的严重程度相关。我们认为，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，同型半胱氨酸升高的患者患有 即使在肾功能完好的患者中，ADPKD也是如此。同型半胱氨酸减少了NO的供应。然而， ADPKD中同型半胱氨酸升高的机制尚不清楚。同型半胱氨酸的升高反映了 NADPH氧化酶4(NOX4)可以调节其代谢的变化。与此相一致，我们发现 在早期疾病的Pkd1RC/RC小鼠中，NOX4上调，同型半胱氨酸增加。药理学 NOX4的减少恢复了同型半胱氨酸代谢，减轻了囊性负荷。甜菜碱，已知会减少 Pkd1RC/RC小鼠血浆同型半胱氨酸、保存的毛细血管指数和降低的囊性负荷。系统性 内皮功能与尿NOX4、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，NOX4的上调是否会重定向 同型半胱氨酸代谢导致NO可获得性和ED的降低，以及ED和 微血管异常对肾脏疾病严重程度的影响尚不清楚。同样，无论标记是否 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 在患者中的情况尚不清楚。我们的中心假设是NOX4的早期上调会重定向 同型半胱氨酸代谢导致其积聚，进而降低NO的可利用性 导致ED和微血管损伤，从而导致ADPKD的严重程度和进展。三个具体的 将追求目标：目标1：测试NOX4的早期上调是否会改变同型半胱氨酸代谢 导致其在ADPKD中积聚。目标2：将测试同型半胱氨酸的积累是否会减少NO 导致勃起功能障碍的可用性，以及勃起功能障碍是否导致微血管损伤和疾病严重程度 和进步。目的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血管病变的严重程度和进展的影响。 ADPKD，并将提供关键的生物学、临床前证据和理论基础，以证明临床试验具有针对性 这种疾病的同型半胱氨酸代谢。

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.