Kidney Week

Abstract: FR-PO587

Sympathetic Nervous System Regulation of the NCC in Dahl Salt-Sensitive Hypertension

Session Information

• Fluid and Electrolytes: Basic - I
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 901 Fluid and Electrolytes: Basic

Authors

• Puleo, Franco J., Boston University, Boston, Massachusetts, United States

Franco J. Puleo,

• Frame, Alissa, Boston University, Boston, Massachusetts, United States

Alissa Frame,

• Wainford, Richard David, Boston University, Boston, Massachusetts, United States

Richard David Wainford,

Background

Studies suggest that sympathetic nervous system (SNS) release of norepinephrine (NE) influences the activity of the sodium chloride cotransporter (NCC) via α₁ and β adrenoceptor pathways. Regulation of the NCC involves a complex network of kinases including WNK1, SPAK, and OXSR1.

Hypothesis: NE stimulates an α₁ adrenoceptor pathway to drive increases in NCC activity that contribute to the development and maintenance of Dahl salt sensitive (DSS) hypertension (SSH).

Methods

Groups of naïve DSS rats and DSS rats given a continuous subcutaneous (s.c.) infusion of terazosin/DMSO (α₁ antagonist, 10mg/kg/day) , or propranolol/DMSO (β antagonist, 10mg/kg/day) were placed on a 21 day normal salt (0.6% NaCl , NS) or high salt (4% NaCl, HS) diet. Separate groups of DSS rats were fed a 42 day HS diet; and on day 21, rats were treated with s.c. saline or terazosin for the remaining 21 days of the diet. Basal MAP, NCC activity (peak natriuresis to hydrochlorothiazide [HCTZ]; 2mg/kg), and the expression of the NCC and its regulatory kinases were assessed via immunoblot on day 21 or day 42 of experimental diet (N=5-6/gp).

Results

DSS rats fed a 21 day HS diet develop SSH and show increases in NCC activity, expression, and its regulatory kinases expression compared to rats on a NS diet. DSS rats fed a 21 day HS diet and treated with α₁ antagonist, terazosin, show attenuated SSH, reduced NCC activity, and expression of NCC and WNK1. A β antagonist, propranolol, did not attenuate DSS SSH. Critically, α₁ adrenoceptor antagonism attenuates SSH, NCC activity/expression, and WNK1 expression in DSS rats with established hypertension.

Conclusion

SNS release of NE activates an α₁ adrenoceptor pathway to drive the development and maintenance of Dahl SSH. Significantly, α₁ adrenoceptor antagonism attenuates the development and maintenance of SSH by evoking downregulation of NCC activity, expression, and regulatory kinase WNK1 expression. Collectively, these findings suggest that NE stimulates an α₁ adrenoceptor pathway involving WNK1 signaling to drive increases in NCC activity and the development and maintenance of SSH in DSS rats.

Funding

• Other NIH Support