The adrenergic regulation of proximal tubular Na⁺/H⁺ exchanger 3 in the rat

Aim: This study in the anaesthetized rat investigated how renal sympathetic nerve activity and catecholamine release influenced NHE3 abundance and activity in proximal tubular brush border membranes using both in vivo and in vitro approaches. Methods: Renal excretory function and brush border NHE3 abundance and activity were measured in rat kidneys which underwent renal denervation, renal nerve electrical stimulation and renal infusion of phenylephrine and the NHE3 inhibitor S1661. NHE3 activity and cell surface abundance were also measured in primary cultures of proximal tubular cells treated with noradrenaline and prazosin. Results: Acute renal denervation caused a natriuresis and diuresis, which occurred with a reduction in NHE3 abundance and activity in the brush border membranes. By contrast, low-level electrical stimulation of the renal innervation causing an antinatriuresis and antidiuresis increased NHE3 activity in the brush border membranes. Intrarenal infusion of phenylephrine caused an antinatriuresis and antidiuresis, while blockade of NHE3 activity, using local infusion of the blocker S1661, caused a natriuresis and diuresis. Exposure of primary cultures of proximal tubular cells to noradrenaline increased brush border NHE3 abundance and activity which was blocked by prior exposure to prazosin, indicating it as an α₁-adrenoceptor-mediated mechanism. Conclusion: Together, these findings demonstrate that the renal sympathetic nerves not only have a direct action to modulate tubular sodium reabsorption via stimulation of the NHE transporter, but also have an indirect effect, whereby NHE3 abundance is increased within the brush border membrane, thereby increasing the capacity for fluid reabsorption.