Pharmacological Npt2a inhibition as a treatment for hyperphosphatemia in chronic kidney disease

药理学 Npt2a 抑制治疗慢性肾病高磷血症

• 批准号: 10293557
• 负责人: Timo Rieg
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293557
• 关键词: Address; Adenine; Affect; Animals; Biochemistry; Biological Process; Calcium; Cardiac; Cardiovascular system; Carrier Proteins; Chronic; Chronic Kidney Failure; Clinical; Confocal Microscopy; Data; Diet; Disease; Dose; Electrolytes; Energy Metabolism; Equilibrium; Excretory function; Exhibits; Failure; General Population; Genetic; Glomerular Filtration Rate; Goals; Homeostasis; Hormonal; Hormones; Hour; Hyperparathyroidism; Hypertension; Impairment; Inorganic Phosphate Transporter; Intake; Intestines; Kidney; Kidney Calculi; Knock-out; Lead; Mediating; Minerals; Modeling; Morphology; Mus; Nephrectomy; Nutrient; Oral; PF4 Gene; PTH gene; Pathology; Patients; Pharmacodynamics; Pharmacology; Physiological; Plasma; Play; Potassium; Prevalence; Process; Protein Biosynthesis; Quality of life; Regulation; Renal function; Role; Secondary Hyperparathyroidism; Signal Transduction; Skeletal Development; Skeletal bone; Sodium Chloride; Specificity; Therapeutic; Time; Veterans; Wild Type Mouse; absorption; apical membrane; blood pressure reduction; bone; cardiovascular risk factor; clinical application; clinically relevant; dietary; experimental study; feeding; fibroblast growth factor 23; improved; in vivo; inhibitor; inorganic phosphate; insight; mortality; mouse model; novel; sodium-phosphate cotransporter proteins; uptake; urinary

The precise regulation of the body's phosphate homeostasis is a critical task. Treatment of hyperphosphatemia, which becomes inevitable in later stages of chronic kidney disease (CKD), is limited to dietary phosphate restriction and oral phosphate binders. Two transport proteins mediate renal phosphate reabsorption, the sodium-phosphate cotransporters Npt2a and Npt2c. The former mediates the majority of renal phosphate reabsorption (70-80%), which is a hormonally regulated process and requires parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). No renal phosphate transport protein has become a pharmacological target yet. We identified that pharmacological inhibition of Npt2a, via a novel orally absorbable Npt2a inhibitor, causes dose-dependent phosphaturia, reductions in plasma phosphate levels and suppression of PTH, but also increases urinary excretion of sodium, chloride and calcium, without affecting urinary potassium excretion, flow rate or pH. These studies show for the first time that a novel Npt2a inhibitor has therapeutic potential in conditions associated with hyperphosphatemia and possibly hyperparathyroidism. In Specific Aim 1, we will determine the pharmacological role of Npt2a inhibition in vivo and ex vivo under control conditions and when animals are challenged by low and high dietary phosphate intake. In Specific Aim 2, we will determine if Npt2a inhibition is a possible treatment option for conditions with impaired phosphate homeostasis and hyperparathyroidism. We will employ (i) adenine-induced CKD and (ii) 5/6th nephrectomy models. Both models show reduced glomerular filtration rate, hyperphosphatemia, hyperparathyroidism, elevated plasma FGF23 levels and hypertension. In Specific Aim 3, we will determine the consequences of renal Npt2a inhibition on intestinal phosphate transport under physiological and pathophysiological conditions (CKD). Since pharmacological Npt2a inhibition and its role for phosphate homeostasis has never been studied before, the results from these studies will be of significant clinical importance because they will: (i) determine pharmacodynamic effects of Npt2a inhibition, (ii) provide insight if targeting Npt2a in CKD can chronically lower plasma phosphate and PTH levels, and (iii) provide insight if Npt2a inhibition can lower blood pressure. This treatment has the potential to improve the quality of life in veterans possibly by improving phosphate homeostasis and reducing cardiovascular mortality.

精确调节身体的磷酸盐稳态是一项关键任务。治疗 高磷酸盐血症，在慢性肾脏疾病（CKD）的晚期不可避免， 仅限于饮食磷酸盐限制和口服磷酸盐结合剂。两种转运蛋白 介导肾磷酸盐重吸收，钠-磷酸盐协同转运蛋白Npt 2a和Npt 2c。 前者介导大部分肾磷酸盐重吸收（70-80%），这是一种 尿道调节过程，需要甲状旁腺激素（PTH）和成纤维细胞生长 因子23（FGF 23）。无肾磷酸盐转运蛋白已成为药理学靶点 呢我们发现，通过一种新的口服可吸收的Npt 2a， 抑制剂，引起剂量依赖性磷酸盐尿，血浆磷酸盐水平降低， 抑制PTH，而且增加钠、氯和钙的尿排泄， 而不影响尿钾排泄、流速或pH值。这些研究表明， 新的Npt 2a抑制剂在与以下疾病相关的疾病中具有治疗潜力的时间 高磷酸盐血症和可能的甲状旁腺功能亢进。在具体目标1中，我们将确定 在对照条件下和当Npt 2a在体内和离体抑制时， 动物受到低和高膳食磷酸盐摄入的挑战。在第二阶段，我们将 确定Npt 2a抑制是否是一种可能的治疗选择， 磷酸盐稳态和甲状旁腺功能亢进。我们将采用（i）腺嘌呤诱导的CKD， (ii)5/6肾切除模型。两种模型均显示肾小球滤过率降低， 高磷酸盐血症、高甲状旁腺素、升高的血浆FGF 23水平和高血压。在 具体目标3，我们将确定肾Npt 2a抑制对肠 生理和病理生理条件下的磷酸盐转运（CKD）。以来 药理学Npt 2a抑制及其对磷酸盐稳态的作用从未被研究过 这些研究的结果将具有重要的临床意义，因为它们将： (i)确定Npt 2a抑制的药效学作用，（ii）提供是否靶向Npt 2a的见解 慢性肾脏病可以长期降低血浆磷酸盐和甲状旁腺素水平，和（iii）提供洞察力，如果Npt 2a 抑制可以降低血压。这种治疗有可能提高生活质量 在退伍军人中可能通过改善磷酸盐稳态和降低心血管死亡率。