Center for Molecular Physiology Research, Children's National Medical Center, Washington, DC 20010, USA.
Hypertension. 2010 Jun;55(6):1431-7. doi: 10.1161/HYPERTENSIONAHA.109.148643. Epub 2010 Apr 19.
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 alpha and gamma 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 alpha and gamma 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.
D(5) 多巴胺受体(D(5)R)缺陷(D(5)(-/-))小鼠患有高血压,而钠摄入量的增加会使其病情加重。本实验旨在验证以下假说,即肾脏钠转运体的失调与 D(5)(-/-) 小鼠的盐敏感性有关。D(5)R 在 D(5)(+/+) 小鼠的肾近端小管、升支粗段、远曲小管、皮质和外髓集合管中表达。在对照的钠饮食中,D(5)(-/-) 小鼠的肾脏 NKCC2(钠-钾-2 氯共转运体)、氯化钠共转运体、上皮钠通道的α和γ亚基的蛋白表达均高于 D(5)(+/+) 小鼠。肾素丰度和尿醛固酮水平相似,但 D(5)(-/-) 小鼠的肾血管紧张素 II 型 1 受体(AT(1)R)蛋白表达增加。高钠饮食进一步增加了 D(5)(-/-) 小鼠的高血压,但对 D(5)(+/+) 小鼠的正常血压没有影响。升高的 NKCC2、氯化钠共转运体、上皮钠通道的α和γ亚基的水平在 D(5)(-/-) 小鼠中持续升高,并且不受高钠饮食和慢性 AT(1)R 阻断(氯沙坦)的影响。D(5)(-/-) 小鼠中,近端钠转运体 NHE3(钠氢交换体 3)和 NaPi2(钠磷酸盐共转运体 2)的表达在高钠饮食中增加;NHE3 的表达增加,但 NaPi2 的表达不受 AT(1)R 阻断的影响。我们的研究结果表明,远曲小管段钠转运体/通道蛋白表达的增加可能是 D(5)R 中断的直接结果,与肾素-血管紧张素-醛固酮系统无关。