Regulation of sodium transport in the proximal tubule by endothelin

Abstract

Human essential hypertension and rodent genetic hypertension are associated with increased sodium transport in the renal proximal tubule and medullary thick ascending limb of Henle. The proximal tubule, which secretes endothelin (ET), expresses the ET(B) receptor. Low (nM) concentrations of ET, via the ET(B) receptor, inhibit sodium and water transport and ATP-driven drug secretion in the proximal tubule. In contrast, very low (pM) and high nM concentrations of ET increase renal proximal sodium transport, but the receptor involved remains to be determined. The natriuretic effect of ET(B) receptor stimulation is impaired in spontaneously hypertensive rats, due in part to a defective interaction with D(3) dopamine and angiotensin II type 1 receptors. Impaired ET(B) receptor function in the renal proximal tubule may be important in the pathogenesis of genetic hypertension.

Figure 1. Interactions among ETB (ETBR), D₃ dopamine (D₃R), and AT₁ (AT₁R) receptors in the regulation of sodium transport in the renal proximal tubule

Stimulation of the AT₁R increases the activity of sodium transporters, sodium exchangers, and the sodium pump (e.g., NaHCO₃ cotransporter, Na⁺H⁺exchanger, and Na⁺-K⁺-ATPase), while their activity is decreased by the stimulation of ETBR and dopamine receptors (e.g., D₁R and D₃R). The ETBR, D₃R, and AT₁R physically interact with each other. Stimulation of the ETBR increases D₃R expression and function but the opposite effect occurs with AT₁R expression and function. The D₃R also negatively regulates AT₁R expression. In contrast, stimulation of the AT₁R increases ETBR expression, in the long-term, and ETBR cell surface expression, in the short-term. Thus, the ETBR synergistically interacts with the D₃R to counterbalance the stimulatory effect of the AT₁R on sodium transport in the renal proximal tubule.