4.4 Review

Npt2a as a target for treating hyperphosphatemia

期刊

BIOCHEMICAL SOCIETY TRANSACTIONS
卷 50, 期 1, 页码 439-446

出版社

PORTLAND PRESS LTD
DOI: 10.1042/BST20211005

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资金

  1. National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK110621]
  2. VA Merit Review Award [IBX004968A]
  3. American Heart Association Transformational Research Award [19TPA34850116]
  4. NIDDK Diabetic Complications Consortium [RRID:SCR_001415, DK076169, DK115255]
  5. American Heart Association postdoctoral fellowship [19POST34400026, 828731]

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Hyperphosphatemia is associated with cardiovascular complications and its management includes oral Pi binders and dietary restrictions. However, these options may be inadequate for patients with chronic kidney disease (CKD). Recent studies propose the inhibition of renal Na+/Pi cotransporter 2a (Npt2a), responsible for most P-i reabsorption, as a potential treatment option. Npt2a inhibitors have been developed and shown to increase urinary P-i excretion and decrease plasma P-i and PTH levels, but their effects on FGF23 are unclear.
Hyperphosphatemia results from an imbalance in phosphate (P) homeostasis. In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications. The current mainstays in the management of hyperphosphatemia are oral P-i binder and dietary P-i restriction. Although these options are employed in patients with chronic kidney disease (CKD), they seem inadequate to correct elevated plasma P-i levels. In addition, a paradoxical increase in expression of intestinal P-i transporter and uptake may occur. Recently, studies in rodents targeting the renal Na+/P-i cotransporter 2a (Npt2a), responsible for similar to 70% of P-i reabsorption, have been proposed as a potential treatment option. Two compounds (PF-06869206 and BAY-767) have been developed which are selective for Npt2a. These Npt2a inhibitors significantly increased urinary P-i excretion consequently lowering plasma P-i and PTH levels. Additionally, increases in urinary excretions of Na+, Cl- and Ca2+ have been observed. Some of these results are also seen in models of reduced kidney function. Responses of FGF23, a phosphaturic hormone that has been linked to the development of left ventricular hypertrophy in CKD, are ambiguous. In this review, we discuss the recent advances on the role of Npt2a inhibition on P-i homeostasis as well as other pleiotropic effects observed with Npt2a inhibition.

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