Journal
JCI INSIGHT
Volume 2, Issue 18, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.92331
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Funding
- NIH [HL135749, HL10880, HL122662, HL122358, HL101681, OD008396]
- MCW NRC/AHW pilot grant [9520217]
- American Heart Association [16EIA26720006, 17SDG33660149]
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Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels K(ir)4.1 (Kcnj10) and K(ir)5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na+ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of K(ir)5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SSKcnj16-/-). SSKcnj16-/- rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia. Electrophysiological recordings of basolateral K+ channels in the collecting ducts isolated from SSKcnj16-/- rats revealed activity of only homomeric K(ir)4.1 channels. K(ir)4.1 expression was upregulated in SSKcnj16-/- rats, but the protein was predominantly localized in the cytosol in SSKcnj16-/- rats. Benzamil, but not hydrochlorothiazide or furosemide, rescued this phenotype from mortality on a high-salt diet. Supplementation of high-salt diet with increased potassium (2% KCl) prevented mortality in SSKcnj16-/- rats and prevented or mitigated hypertension in SSKcnj16-/- or control SS rats, respectively. Our results demonstrate that K(ir)5.1 channels are key regulators of renal salt handling in SS hypertension.
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