Upregulation of Renal Sodium Transporters in D 5 Dopamine Receptor–Deficient Mice

Abstract

D ₅ dopamine receptor (D ₅ R)-deficient (D ₅ ^−/− ) mice have hypertension that is aggravated by an increase in sodium intake. The present experiments were designed to test the hypothesis that a dysregulation of renal sodium transporters is related to the salt sensitivity in D ₅ ^−/− mice. D ₅ R was expressed in the renal proximal tubule, thick ascending limb, distal convoluted tubule, and cortical and outer medullary collecting ducts in D ₅ ^+/+ mice. On a control Na ⁺ diet, renal protein expressions of NKCC2 (sodium-potassium-2 chloride cotransporter), sodium chloride cotransporter, and α and γ subunits of the epithelial sodium channel were greater in D ₅ ^−/− than in D ₅ ^+/+ mice. Renal renin abundance and urine aldosterone levels were similar but renal angiotensin II type 1 receptor (AT ₁ R) protein expression was increased in D ₅ ^−/− mice. An elevated Na ⁺ diet increased further the elevated blood pressure of D ₅ ^−/− mice but did not affect the normal blood pressure of D ₅ ^+/+ mice. The increased levels of NKCC2, sodium chloride cotransporter, and α and γ subunits of the epithelial sodium channel persisted with the elevated Na ⁺ diet and unaffected by chronic AT ₁ R blockade (losartan) in D ₅ ^−/− mice. The expressions of proximal sodium transporters NHE3 (sodium hydrogen exchanger type 3) and NaPi2 (sodium phosphate cotransporter type 2) were increased by the elevated Na ⁺ diet in D ₅ ^−/− mice; the increased expression of NHE3 but not NaPi2 was abolished by AT ₁ R blockade. Our findings suggest that the increased protein expression of sodium transporters/channels in distal nephron segments may be the direct consequence of the disruption of D ₅ R, independent of the renin–angiotensin aldosterone system.