Upregulation of Renal Sodium Transporters in D5 Dopamine Receptor–Deficient Mice

D5 dopamine receptor (D5R)-deficient (D5−/−) 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 D5−/− mice. D5R was expressed in the renal proximal tubule, thick ascending limb, distal convoluted tubule, and cortical and outer medullary collecting ducts in D5+/+ mice. On a control Na+ diet, renal protein expressions of NKCC2 (sodium-potassium-2 chloride cotransporter), sodium chloride cotransporter, and &agr; and &ggr; subunits of the epithelial sodium channel were greater in D5−/− than in D5+/+ mice. Renal renin abundance and urine aldosterone levels were similar but renal angiotensin II type 1 receptor (AT1R) protein expression was increased in D5−/− mice. An elevated Na+ diet increased further the elevated blood pressure of D5−/− mice but did not affect the normal blood pressure of D5+/+ mice. The increased levels of NKCC2, sodium chloride cotransporter, and &agr; and &ggr; subunits of the epithelial sodium channel persisted with the elevated Na+ diet and unaffected by chronic AT1R blockade (losartan) in D5−/− 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 D5−/− mice; the increased expression of NHE3 but not NaPi2 was abolished by AT1R 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 D5R, independent of the renin–angiotensin aldosterone system.

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