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: 10007044
• 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/10007044
• 关键词: Address; Adenine; Affect; Animals; Bioavailable; 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/antagonist; 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.

精确调节体内的磷酸盐动态平衡是一项关键任务。治疗 高磷血症，这是慢性肾脏疾病(CKD)后期不可避免的， 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 介导肾脏磷酸盐重吸收，钠-磷酸共转运体Npt2a和Npt2c。 前者介导了肾脏磷酸盐的大部分重吸收(70%-80%)，这是一种 激素调节的过程，需要甲状旁腺激素(PTH)和成纤维细胞生长 因子23(FGF23)。没有肾脏磷酸转运蛋白成为药理靶点 现在还不行。我们发现，Npt2a的药理抑制作用是通过一种新的口服吸收的Npt2a 抑制剂，导致剂量依赖性磷酸尿，血浆磷水平下降和 抑制甲状旁腺激素，但也增加尿钠、氯和钙的排泄， 不影响尿钾排泄、尿流率或pH。这些研究首次表明 一种新型Npt2a抑制剂在与以下疾病相关的条件下具有治疗潜力的时间 高磷血症可能还有甲状旁腺功能亢进症。在具体目标1中，我们将确定 Npt2a抑制在体内外对照条件下的药理作用 动物面临着饮食中磷酸盐摄入量过高和过低的挑战。在具体目标2中，我们将 确定抑制Npt2a是否是治疗受损性疾病的可能选择 磷酸盐稳态和甲状旁腺机能亢进症。我们将采用(I)腺嘌呤诱导的CKD和 (2)5/6肾切除模型。两种模型都显示肾小球滤过率降低， 高磷血症、甲状旁腺功能亢进症、血浆FGF23水平升高和高血压。在……里面 具体目标3，我们将确定肾脏Npt2a抑制对肠道的影响 生理和病理生理条件下的磷酸盐运输(CKD)。自.以来 药物对Npt2a的抑制及其对磷酸盐稳态的作用从未被研究过 以前，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Npt2a抑制的药效学效应；(Ii)提供是否针对Npt2a的洞察力 慢性肾脏病可以慢性降低血磷和甲状旁腺素水平，以及(Iii)提供洞察力是否Npt2a 抑制可以降低血压。这种治疗方法有可能提高生活质量。 在退伍军人中，可能是通过改善磷酸盐稳态和降低心血管死亡率。