Activation/deactivation of renal Na ⁺ ,K ⁺ ‐ATPase: a final common pathway for regulation of natriuresis

Abstract

Renal sodium metabolism, a major determinant of blood pressure, is regulated with great precision by a variety of endocrine, autocrine, and neuronal factors. Although these factors are known to regulate sodium metabolism by affecting the rate of tubular sodium reabsorption, the molecular mechanisms by which they act are poorly understood. Na+,K(+)-ATPase plays a pivotal role for sodium reabsorption in all tubular segments. The activity of this enzyme can be dynamically regulated by phosphorylation and dephosphorylation. Here we summarize both old and new evidence that several major substances believed to be involved in the regulation of sodium metabolism and blood pressure, i.e., the antidiuretic agents angiotensin II and norepinephrine, and the diuretic agents dopamine and atrial natriuretic peptide (ANP), may achieve their effects through a common pathway that involves reversible activation/deactivation of renal tubular Na+,K(+)-ATPase. Regulation of Na+,K(+)-ATPase activity was studied using a preparation of single proximal tubule (PT) segments, dissected from rat kidneys. Na+,K(+)-ATPase activity was stimulated by angiotensin II and the alpha-adrenergic agonist, oxymetazoline, at physiological, nonsaturating Na+ concentrations. These stimulatory effects were blocked by dopamine and ANP as well as by their respective second messengers, cAMP and cGMP. They were also blocked by the specific protein phosphatase 2B inhibitor FK506. These results indicate that regulation of sodium excretion by norepinephrine, angiotensin II, dopamine, and ANP can be accounted for by a bidirectionally regulated intracellular protein phosphorylation cascade that modulates the activity of renal tubular Na+,K(+)-ATPase.

C-peptide stimulates rat renal tubular Na+, K+-ATPase activity in synergism with neuropeptide Y

“…The effects of C-peptide on Na +, K+-ATPase activity resemble in many aspects those of norepinephrine (acting on c~-adrenergic receptors), angiotensin II, and NPY [12,13]. Like C-peptide, all of these first messengers increase the sodium affinity of PCT Na +, K +-ATPase.…”

“…The above considerations prompted us to investigate the possible influence of C-peptide on Na +, K +-ATPase in proximal tubular segments from the rat nephron, a well-defined model [13,14]. Having then found an effect of C-peptide, we subsequently studied the subcellular mechanisms for its action as well as its possible interaction with other hormones known to stimulate Na +, K +-ATPase activity.…”

“…This results in a bidirectional regulation of tubular Na +, K +-ATPase activity which allows Na § reabsorption to be regulated with great precision [13,34]. The finding that cAMP abolished the stimulatory effects of Cpeptide may imply that C-peptide participates in this bidirectional regulation of proximal tubular Na + reabsorption by antinatriuretic and natriuretic hormones.…”

“…Moreover, FK 506 -a specific inhibitor of PP2B [21] -completely blocked the stimulatory effect of C-peptide. The PP2B is of central importance for the regulation of renal Na +, K+-ATPase activity [13,34]. Stimulation of Na +, K +-ATPase activity by either a-adrenergic agonists, angiotensin II and/or NPY is completely blocked in the presence of FK 506.…”

Mutation of the Protein Kinase C Phosphorylation Site on Rat α1 Na+,K+-ATPase Alters Regulation of Intracellular Na+ and pH and Influences Cell Shape and Adhesiveness

“…For this reason the pump has often been considered to have a passive role in the regulation of cellular Na ϩ and K ϩ homeostasis (4). Recently it has been shown that Na ϩ ,K ϩ -ATPase activity can be regulated by hormones, second messengers, protein kinase A (PKA) 1 and protein kinase C (PKC) (5)(6)(7)(8). Together, these various results suggest that the response of Na ϩ ,K ϩ -ATPase to altered ion levels is hormonally modulated allowing for greater versatility in the regulation of cellular homeostasis.…”