Journal
FASEB JOURNAL
Volume 33, Issue 4, Pages 5067-5075Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201802257R
Keywords
pH regulation; control of breathing; ion channels
Categories
Funding
- U.S. National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) [HL007852, HL122358, HL135749]
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Acute and chronic homeostatic pH regulation is critical for the maintenance of optimal cellular function. Renal mechanisms dominate global pH regulation over longer time frames, and rapid adjustments in ventilation compensate for acute pH and CO2 changes. Ventilatory CO2 and pH chemoreflexes are primarily determined by brain chemoreceptors with intrinsic pH sensitivity likely driven by K+ channels. Here, we studied acute and chronic pH regulation in Kcnj16 mutant Dahl salt-sensitive (SSKcnj16-/-) rats; Kcnj16 encodes the pH-sensitive inwardly rectifying K+ 5.1 (Kir5.1) channel. SSKcnj16-/- rats hyperventilated at rest, likely compensating for a chronic metabolic acidosis. Despite their resting hyperventilation, SSKcnj16-/- rats showed up to 45% reduction in the ventilatory response to graded hypercapnic acidosis vs. controls. SSKcnj16-/- rats chronically treated with bicarbonate or the carbonic anhydrase inhibitor hydrochlorothiazide had partial restoration of arterial pH, but there was a further reduction in the ventilatory response to hypercapnic acidosis. SSKcnj16-/- rats also had a nearly absent hypoxic ventilatory response, suggesting major contributions of Kir5.1 to O-2- and CO2-dependent chemoreflexes. Although previous studies demonstrated beneficial effects of a high-K+ diet (HKD) on cardiorenal phenotypes in SSKcnj16-/- rats, HKD failed to restore the observed ventilatory phenotypes. We conclude that Kir5.1 is a key regulator of renal H+ handling and essential for acute and chronic regulation of arterial pH as determinants of the ventilatory CO2 chemoreflex.
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