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.

人体磷酸盐稳态的精确调节是一项关键任务。处理 在慢性肾脏疾病（CKD）的后期不可避免的高磷酸血症， 仅限于饮食磷酸盐限制和口服磷酸盐粘合剂。两个转运蛋白 介导肾磷酸盐吸收，磷酸钠共转运蛋白NPT2A和NPT2C。 前者介导了大多数肾磷酸盐重吸收（70-80％），这是 荷尔蒙调节过程，需要甲状旁腺激素（PTH）和成纤维细胞生长 因子23（FGF23）。没有肾磷酸转运蛋白已成为药理靶标 然而。我们通过新颖的可吸收NPT2A确定了NPT2A的药理抑制作用 抑制剂，导致剂量依赖性磷，血浆磷酸盐水平的降低和 抑制PTH，但也会增加钠，氯化物和钙的尿排泄， 不影响尿钾排泄，流速或pH。这些研究表明了第一个 新型NPT2A抑制剂在与之相关的条件下具有治疗潜力的时间 高磷酸血症，可能是甲状旁腺功能亢进。在特定目标1中，我们将确定 NPT2a在对照条件下的体内和体内抑制作用的药理作用以及何时 动物受到低饮食磷酸盐摄入量的挑战。在特定的目标2中，我们将 确定NPT2A抑制是否是患有受损状况的治疗选择 磷酸盐稳态和甲状旁腺功能亢进。我们将雇用（i）腺嘌呤引起的CKD和 （ii）5/6肾切除术模型。两种模型均显示肾小球过滤率降低， 高磷酸血症，甲状旁腺功能亢进，血浆FGF23水平升高和高血压。在 特定目标3，我们将确定肾脏NPT2A抑制对肠的后果 在生理和病理生理条件下（CKD）下的磷酸盐转运。自从 从未研究过药理学NPT2A抑制及其在磷酸盐稳态中的作用 以前，这些研究的结果将具有重要的临床重要性，因为它们将： （i）确定NPT2A抑制的药效学效应，（ii）如果针对NPT2A，则提供洞察力 在CKD中，可以长期降低血浆磷酸盐和PTH水平，（iii）提供洞察力，如果NPT2A 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并降低心血管死亡率。