The precise regulation of the body's phosphate homeostasis is a critical task. Treatment of hyperphosphatemia, which becomes inevitable in the 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 the adenine-induced CKD model and 5/6th nephrectomy model. Both models show reduced glomerular filtration rate, hyperphosphatemia, hyperparathyroidism, elevated plasma FGF23 levels and hypertension. Since Npt2a inhibition and its role for phosphate homeostasis has never been studied before under physiological and pathophysiological conditions, 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/hyperparathyroidism can chronically lower plasma phosphate and PTH levels, and (iii) provide insight if Npt2a inhibition can lower blood pressure.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 06/30/2022|