Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, U.S.A.
Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, U.S.A.
Clin Sci (Lond). 2023 Dec 22;137(24):1789-1804. doi: 10.1042/CS20230313.
Angiotensin receptor blockers (ARBs) are the first-line treatment for hypertension; they act by inhibiting signaling through the angiotensin 1 receptor (AT1R). Recently, a novel biased AT1R agonist, TRV120027 (TRV), which selectively activates the β-arrestin cascade and blocks the G-protein-coupled receptor pathway has been proposed as a potential blood pressure medication. Here, we explored the effects of TRV and associated β-arrestin signaling in podocytes, essential cells of the kidney filter. We used human podocyte cell lines to determine β-arrestin's involvement in calcium signaling and cytoskeletal reorganization and Dahl SS rats to investigate the chronic effects of TRV administration on glomerular health. Our experiments indicate that the TRV-activated β-arrestin pathway promotes the rapid elevation of intracellular Ca2+ in a dose-dependent manner. Interestingly, the amplitude of β-arrestin-mediated Ca2+ influx was significantly higher than the response to similar Ang II concentrations. Single-channel analyses show rapid activation of transient receptor potential canonical (TRPC) channels following acute TRV application. Furthermore, the pharmacological blockade of TRPC6 significantly attenuated the β-arrestin-mediated Ca2+ influx. Additionally, prolonged activation of the β-arrestin pathway in podocytes resulted in pathological actin cytoskeleton rearrangements, higher apoptotic cell markers, and augmented glomerular damage. TRV-activated β-arrestin signaling in podocytes may promote TRPC6 channel-mediated Ca2+ influx, foot process effacement, and apoptosis, possibly leading to severe defects in glomerular filtration barrier integrity and kidney health. Under these circumstances, the potential therapeutic application of TRV for hypertension treatment requires further investigation to assess the balance of the benefits versus possible deleterious effects and off-target damage.
血管紧张素受体阻滞剂 (ARBs) 是治疗高血压的一线药物；它们通过抑制血管紧张素 1 受体 (AT1R) 的信号传递来发挥作用。最近，一种新型的偏向性 AT1R 激动剂 TRV120027 (TRV) 被提出作为一种潜在的降压药物，它选择性地激活β-arrestin 级联反应并阻断 G 蛋白偶联受体途径。在这里，我们研究了 TRV 及其相关的β-arrestin 信号在足细胞中的作用，足细胞是肾脏滤器的重要细胞。我们使用人足细胞细胞系来确定β-arrestin 在钙信号和细胞骨架重排中的作用，并使用 Dahl SS 大鼠来研究 TRV 给药对肾小球健康的慢性影响。我们的实验表明，TRV 激活的β-arrestin 途径以剂量依赖的方式促进细胞内 Ca2+的快速升高。有趣的是，β-arrestin 介导的 Ca2+内流的幅度明显高于对类似 Ang II 浓度的反应。单通道分析表明，急性 TRV 应用后，瞬时受体电位经典型 (TRPC) 通道迅速激活。此外，TRPC6 的药理学阻断显著减弱了β-arrestin 介导的 Ca2+内流。此外，足细胞中β-arrestin 途径的长期激活导致病理性肌动蛋白细胞骨架重排、更高的凋亡细胞标志物和增强的肾小球损伤。TRV 激活的足细胞中的β-arrestin 信号可能促进 TRPC6 通道介导的 Ca2+内流、足突消失和细胞凋亡，可能导致肾小球滤过屏障完整性和肾脏健康的严重缺陷。在这种情况下，TRV 治疗高血压的潜在治疗应用需要进一步研究，以评估其益处与可能的有害影响和脱靶损伤之间的平衡。
