Cellular mechanisms for bi-directional regulation of tubular sodium reabsorption

Abstract

The molecular mechanisms underlying the regulation of sodium excretion are incompletely known. Here we propose a general model for a bi-directional control of tubular sodium transporters by natriuretic and antinatriuretic factors. The model is based on experimental data from studies on the regulation of the activity of Na+,K+-ATPase, the enzyme that provides the electrochemical gradient necessary for tubular reabsorption of electrolytes and solutes in all tubular segments. Regulation is carried out to a large extent by autocrine and paracrine factors. Of particular interest are the two catecholamines, dopamine and norepinephrine. Dopamine is produced in proximal tubular cells and inhibits Na+,K+-ATPase activity in several tubule segments. Renal dopamine availability is regulated by the degrading enzyme, catechol-O-methyl transferase. Renal sympathetic nerve endings contain norepinephrine and neuropeptide Y (NPY). Activation of alpha-adrenergic receptors increase and activation of beta-adrenergic receptors decrease Na+,K+-ATPase activity. alpha-Adrenergic stimulation increases the Na+ affinity of the enzyme and thereby the driving force for transcellular Na+ transport. NPY acts as a master hormone by synergizing the alpha- and antagonizing the beta-adrenergic effects. Dopamine and norepinephrine control Na+,K+-ATPase activity by exerting opposing forces on a common intracellular signaling system of second messengers, protein kinases and protein phosphatases, ultimately determining the phosphorylation state of Na+,K+-ATPase and thereby its activity. Important crossroads in this network are localized and functionally defined. Phosphorylation sites for protein kinase A and C have been identified and their functional significance has been verified.

Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D 1A Receptor in Obese Zucker Rats

“…In plasma membranes from obese control rats, fenoldopam did not stimulate [ 35 3C) was not significantly different from that in lean control rats (Figures 2A and 3A). Rosiglitazone treatment of obese rats restored increase in specific [ 3 H] SCH-23390 binding ( Figure 2D) and D 1A receptor protein density ( Figure 3D) in plasma membranes when proximal tubules were treated with dopamine compared with KHB A. A-treated or dopamine-treated proximal tubules was similar in lean control and treated rats.…”

“…21 It is possible that rosiglitazone, a PPAR␥ agonist, increases transcription of one or several G proteins, resulting in increased levels of total G-protein pool. It is also possible that the ratio of high-affinity (GTP-bound) to low-affinity (GDPbound) G proteins is increased after rosiglitazone treatment, resulting in an increase in basal [ 35 Rosiglitazone improves insulin sensitivity in animals as well as patients. [22][23][24][25] This has been evaluated by oral glucose tolerance test or hyperinsulinemic-euglycemic clamp techniques.…”

“…Moreover, dopamine enhances the effects of other natriuretic hormones, such as atrial natriuretic peptide and counteracts the effects of antinatriuretic hormones such as angiotensin II. 35 Increased sodium retention in obesity may be owing to loss of dopaminergic control over antinatriuretic and natriuretic hormones. The loss of dopaminergic control could result from impaired D 1A receptor G-protein coupling, recruitment, and function caused by insulin resistance.…”

“…First, plasma membranes were prepared from vehicle-and dopamine-treated proximal tubules and were used for fenoldopamstimulated [ 35 …”

Acute Volume Expansion and Salt-Loading Studies in Rats

“…Circulating atrial natriuretic peptide (ANP), a natriuretic peptide induced by AcVE, has been implicated in the escape phenomenon of mineralocorticoid excess, a frequently employed model for chronic volume expansion [3, 4]. Dopamine has been extensively investigated both at the cellular level [5, 6] and whole kidney level [7, 8] and has certainly been shown to be closely linked to the natriuresis of both AcVE and salt loading [6, 7]. Resetting of tubuloglomerular feedback has been shown to occur during chronic salt loading and this has been attributed to the binding of endogenous dopamine to luminal D1 receptors on the macula densa cells [9].…”