Na/K-ATPase in the renal proximal tubule cell: classic & novel roles in sodium handling.

The cell membrane Na/K-ATPase (NKA), the archetypal P-type ATPase, is the enzymatic complex that hydrolyzes ATP to transport Na+ and K+ against their transmembrane electrochemical gradients. While it has long been known that NKAs are essential to homeostasis in animal cells, active research continues to unveil the depth and complexity of their tissue-specific functions as ion-pumps and receptors for endogenous cardiotonic steroids (eCTS). Sodium handling in the renal proximal tubule (RPT), a major regulator of systemic salt and water balance and blood pressure, is among the cell-specific NKA functions that have been the most studied to date. A rather comprehensive and integrated view of the biological pathways involved has emerged in physiological conditions and in disease states such as salt-sensitive hypertension and chronic kidney disease. Increasingly, sex-specific differences in the distribution and activity of NKA and other transporters along the nephron are reported, with functional links to differences in sodium handling and disease susceptibility. Following a brief overview of NKAs' molecular composition and functions, this review focuses on the molecular structure, regulatory mechanisms, and classic and novel roles of NKA in the RPT, emphasizing its importance in sodium handling, blood pressure regulation, and renal disease.