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: 10553084
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553084
• 关键词: Address; Adenine; Affect; Animals; Biochemistry; Biological Availability; Biological Process; Calcium; Cardiac; Cardiovascular system; Carrier Proteins; Chlorides; 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; Knockout Mice; Mediating; Minerals; Modeling; Morphology; Nephrectomy; Nutrient; Oral; PF4 Gene; PTH gene; Pathology; Patients; Pharmacodynamics; Physiological; Plasma; Play; Potassium; Prevalence; Process; Protein Biosynthesis; Quality of life; Regulation; Renal function; Role; Secondary Hyperparathyroidism; Signal Transduction; Skeletal Development; Skeletal bone; Sodium; 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; pharmacologic; sodium-phosphate cotransporter proteins; symporter; 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.

对人体磷酸盐稳态的精确调节是一项关键任务。治疗