Institute of Clinical Pharmacology and Toxicology (A.K., A.S., E.M., D.K.-G., J.B., R.K.), Charité-Universitätsmedizin Berlin, Germany.
Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (A.K., M.B., B.P., S.K., T.G., T.N., D.P.).
Hypertension. 2023 Apr;80(4):771-782. doi: 10.1161/HYPERTENSIONAHA.122.20392. Epub 2023 Jan 30.
Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Upregulation of COX2 (cyclooxygenase 2) and prostaglandin E (PGE) was linked to podocyte damage in GH. We explored the potential renoprotective effects of either separate or combined pharmacological blockade of EP2 (PGE receptor type 2) and EP4 (PGE receptor type 4) in GH.
We conducted in vivo studies in a transgenic zebrafish model () suitable for analysis of glomerular filtration barrier function and a genetic rat model with GH, albuminuria, and upregulation of PGE. Similar pharmacological interventions and primary outcome analysis on albuminuria phenotype development were conducted in both model systems.
Stimulation of zebrafish embryos with PGE induced an albuminuria-like phenotype, thus mimicking the suggested PGE effects on glomerular filtration barrier dysfunction. Both separate and combined blockade of EP2 and EP4 reduced albuminuria phenotypes in zebrafish and rat models. A significant correlation between albuminuria and podocyte damage in electron microscopy imaging was identified in the rat model. Dual blockade of both receptors showed a pronounced synergistic suppression of albuminuria. Importantly, this occurred without changes in arterial blood pressure, glomerular filtration rate, or tissue oxygenation in magnetic resonance imaging, while RNA sequencing analysis implicated a potential role of circadian clock genes.
Our findings confirm a role of PGE in the development of albuminuria in GH and support the renoprotective potential of combined pharmacological blockade of EP2 and EP4 receptors. These data support further translational research to explore this therapeutic option and a possible role of circadian clock genes.
肾小球高滤过（GH）是高血压患者白蛋白尿发展的一个重要机制。环氧化酶 2（COX2）和前列腺素 E（PGE）的上调与 GH 中的足细胞损伤有关。我们探讨了单独或联合阻断 EP2（PGE 受体 2）和 EP4（PGE 受体 4）对 GH 中潜在的肾脏保护作用。
我们在一种适合分析肾小球滤过屏障功能的转基因斑马鱼模型和一种 GH、白蛋白尿和 PGE 上调的遗传大鼠模型中进行了体内研究。在这两种模型系统中，我们对类似的药理学干预和白蛋白尿表型发展的主要结果进行了分析。
用 PGE 刺激斑马鱼胚胎会引起类似白蛋白尿的表型，从而模拟了 PGE 对肾小球滤过屏障功能障碍的影响。单独和联合阻断 EP2 和 EP4 均可减少斑马鱼和大鼠模型中的白蛋白尿表型。在大鼠模型中，电子显微镜成像中的白蛋白尿与足细胞损伤之间存在显著相关性。两种受体的双重阻断显示出明显的协同抑制白蛋白尿作用。重要的是，这一作用发生时不会改变磁共振成像中的动脉血压、肾小球滤过率或组织氧合，而 RNA 测序分析表明，昼夜节律基因可能发挥作用。
我们的研究结果证实了 PGE 在 GH 中白蛋白尿发展中的作用，并支持联合阻断 EP2 和 EP4 受体的肾脏保护作用。这些数据支持进一步的转化研究，以探索这种治疗选择和昼夜节律基因的可能作用。
