Journal
CLINICAL SCIENCE
Volume 133, Issue 24, Pages 2449-2461Publisher
PORTLAND PRESS LTD
DOI: 10.1042/CS20190876
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Funding
- National Institutes of Health [R35 HL135749, P01 HL116264, R56 DK121750, F31 DK122647, R01 HL122358]
- American Heart Association [16EIA26720006, 17SDG33660149]
- Michael H. Keelan, Jr, MD, Research Foundation Grant
- Cardiovascular Center at the Medical College of Wisconsin
- Department of Veteran Affairs [I01 BX004024]
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K(ir)5.1 (encoded by the Kcnj16 gene) is an inwardly rectifying K+ (K-ir) channel highly expressed in the aldosterone-sensitive distal nephron of the kidney, where it forms a functional channel with K(ir)4.1. K(ir)4.1/K(ir)5.1 channels are responsible for setting the transepithelial voltage in the distal nephron and collecting ducts and are thereby major determinants of fluid and electrolyte distribution. These channels contribute to renal blood pressure control and have been implicated in salt-sensitive hypertension. However, mechanisms pertaining to the impact of K(ir)4.1/K(ir)5.1-mediated K+ transport on the renin-angiotensin-aldosterone system (RAAS) remain unclear. Herein, we utilized a knockout of Kcnj16 in the Dahl salt-sensitive rat (SSKcnj16-/-) to investigate the relationship between K(ir)5.1 and RAAS balance and function in the sensitivity of blood pressure to the dietary Na+/K( )(+)ratio. The knockout of Kcnj16 caused substantial elevations in plasma RAAS hormones (aldosterone and angiotensin peptides) and altered the RAAS response to changing the dietary Na+/K+ ratio. Blocking aldosterone with spironolactone caused rapid mortality in SSKcnj16-/- rats. Supplementation of the diet with high K+ was protective against mortality resulting from aldosterone-mediated mechanisms. Captopril and losartan treatment had no effect on the survival of SSKcnj16-/- rats. However, neither of these drugs prevented mortality of SSKcnj16-/- rats when switched to high Na+ diet. These studies revealed that the knockout of Kcnj16 markedly altered RAAS regulation and function, suggesting K(ir)5.1 as a key regulator of the RAAS, particularly when exposed to changes in dietary sodium and potassium content.
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