Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt-Sensitive Hypertension.
Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt-Sensitive Hypertension.
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DOI：
10.1161/hypertensionaha.120.15928
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Wainford RD
中科院分区：
文献类型：
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作者：
Puleo F;Kim K;Frame AA;Walsh KR;Ferdaus MZ;Moreira JD;Comsti E;Faudoa E;Nist KM;Abkin E;Wainford RD
Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure (BP). The mechanism(s) by which excessive sympathetic nervous system release of norepinephrine (NE) influences renal sodium reabsorption is unclear. However, studies demonstrate that NE can stimulate the activity of the sodium chloride cotransporter (NCC) and promote the development of salt-sensitive hypertension (SSH). The adrenergic signaling pathways governing NCC activity remain a significant source of controversy with opposing studies suggesting a central role of upstream α1- and/or β-adrenoceptors in the canonical regulatory pathway involving with-no-lysine kinases (WNKs), STE20/SPS1-related proline alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1). In our previous study, α1-adrenoceptor antagonism in NE-infused male Sprague-Dawley rats prevented the development of NE-evoked SSH in part by suppressing NCC activity and expression. In these studies, we used selective adrenoceptor antagonism in male Dahl Salt-Sensitive (DSS) rats to test the hypothesis that NE-mediated activation of the NCC in Dahl SSH occurs via an α1-adrenoceptor dependent pathway. A high salt diet evoked significant increases in NCC activity, expression, and phosphorylation in DSS rats that developed SSH. Increases were associated with a dysfunctional WNK1/4 dynamic and a failure to suppress SPAK/OxSR1 activity. α1-adrenoceptor antagonism initiated prior to high salt intake or following the establishment of SSH attenuated BP in part by suppressing NCC activity, expression, and phosphorylation. Collectively our findings support the existence of a NE-activated α1-adrenoceptor gated pathway that relies on WNK/SPAK/OxSR1 signaling to regulate NCC activity in SSH.
