The Core Laboratory for Clinical Research, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China.
Department of Nephrology, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China.
Hypertens Res. 2024 Aug;47(8):2144-2156. doi: 10.1038/s41440-024-01724-5. Epub 2024 May 22.
To explore the mechanism of the hypertension in dopamine receptor-4 (Drd4) null mice, we determined the salt sensitivity and renal sodium transport proteins in Drd4 and Drd4 mice with varied salt diets. On normal NaCl diet (NS), mean arterial pressures (MAP, telemetry) were higher in Drd4 than Drd4; Low NaCl diet (LS) tended to decrease MAP in both strains; high NaCl diet (HS) elevated MAP with sodium excretion decreased and pressure-natriuresis curve shifted to right in Drd4 relative to Drd4 mice. Drd4 mice exhibited increased renal sodium-hydrogen exchanger 3 (NHE3), sodium-potassium-2-chloride cotransporter (NKCC2), sodium-chloride cotransporter (NCC), and outer medullary α-epithelial sodium channel (αENaC) on NS, decreased NKCC2, NCC, αENaC, and αNa-K-ATPase on LS, and increased αENaC on HS. NKCC2, NCC, αENaC, and αNa-K-ATPase in plasma membrane were greater in Drd4 than in Drd4 mice with HS. D4R was expressed in proximal and distal convoluted tubules, thick ascending limbs, and outer medullary collecting ducts and colocalized with NKCC2 and NCC. The phosphorylation of NKCC2 was enhanced but ubiquitination was reduced in the KO mice. There were no differences between the mouse strains in serum aldosterone concentrations and urinary dopamine excretions despite their changes with diets. The mRNA expressions of renal NHE3, NKCC2, NCC, and αENaC on NS were not altered in Drd4 mice. Thus, increased protein expressions of NHE3, NKCC2, NCC and αENaC are associated with hypertension in Drd4 mice; increased plasma membrane protein expression of NKCC2, NCC, αENaC, and αNa-K-ATPase may mediate the salt sensitivity of Drd4 mice.
为了探究多巴胺受体-4（Drd4）缺失小鼠高血压的发生机制，我们利用不同盐饮食，检测了 Drd4 缺失和野生型小鼠的盐敏感性和肾脏钠转运蛋白。在正常盐饮食（NS）下，Drd4 缺失小鼠的平均动脉压（MAP，遥测）高于野生型；低盐饮食（LS）可降低两种品系的 MAP；高盐饮食（HS）可升高 MAP，同时钠排泄减少，压力-钠排泄曲线向 Drd4 缺失小鼠右移。在 NS 时，Drd4 缺失小鼠的肾脏钠-氢交换蛋白 3（NHE3）、钠-钾-2-氯协同转运蛋白（NKCC2）、钠-氯协同转运蛋白（NCC）和外髓质α上皮钠通道（αENaC）表达增加，在 LS 时 NKCC2、NCC、αENaC 和 αNa-K-ATP 酶表达减少，HS 时 αENaC 表达增加。HS 时，Drd4 缺失小鼠的 NKCC2、NCC、αENaC 和 αNa-K-ATP 酶在质膜中的表达高于野生型。D4R 在外髓质集合管和远曲小管、近端和远端卷曲小管、升支粗段表达，并与 NKCC2 和 NCC 共定位。KO 小鼠中 NKCC2 的磷酸化增强，但泛素化减少。尽管饮食改变了，但两种小鼠品系的血清醛固酮浓度和尿多巴胺排泄量没有差异。NS 时，Drd4 缺失小鼠的肾脏 NHE3、NKCC2、NCC 和 αENaC 的 mRNA 表达没有改变。因此，Drd4 缺失小鼠中 NHE3、NKCC2、NCC 和 αENaC 的蛋白表达增加与高血压有关；NKCC2、NCC、αENaC 和 αNa-K-ATP 酶的质膜蛋白表达增加可能介导了 Drd4 缺失小鼠的盐敏感性。
