Genetic mutation of Kcnj16 identifies Kir5.1‐containing channels as key regulators of acute and chronic pH homeostasis

Abstract

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 Kcnj 16 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 O2‐ 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.—Puissant, M. M., Muere, C.., Levchenko, V., Manis, A. D., Martino, P., Forster, H. V., Palygin, O., Staruschenko, A., Hodges, M. R. Genetic mutation of Kcnj16 identifies Kir5.1‐containing channels as key regulators of acute and chronic pH homeostasis. FASEB J. 33, 5067–5075 (2019). http://www.fasebj.org

Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat

“…However, the origins of audiogenic seizures are largely thought to arise from subcortical brain regions, including the brainstem ( 35 ), and behavioral patterns in SS Kcnj16–/– rats indicate generalized rather than partial seizures, as behaviors are exhibited symmetrically in both sides of the body. The presence of audiogenic seizures in SS Kcnj16–/– rats combined with our previous findings of deficits in CNS-driven respiratory chemoreflexes strongly support a major role for K ir 5.1 in vital brainstem functions ( 20 ). Moreover, K ir 5.1 has been shown to be more highly expressed in the brainstem compared with the cortex ( 36 ).…”

“…The presence of audiogenic seizures in SS Kcnj16-/rats combined with our previous findings of deficits in CNS-driven respiratory chemoreflexes strongly support a major role for Kir5.1 in vital brainstem functions (20). Moreover, Kir5.1 has been shown to be more highly expressed in the brainstem compared to the cortex (35).…”

“…We recently showed that mutations of Kcnj16 alter K + homeostasis and can be protective against salt-induced hypertension ( 18 ). In addition, our previous work indicates that K ir 5.1 expressed in brainstem respiratory nuclei contributes to acute pH homeostasis via the ventilatory chemoreflex ( 20 ). Studies in Kcnj16 -knockout mice have also reported a reduction in central chemosensitivity and/or impaired chemoreflexes ( 28 , 29 ) and other similar phenotypes, including metabolic acidosis, hypokalemia, and low body weight ( 30 ).…”

“…This difference is very likely due to the hypertensive genetic background of the Dahl SS rat. In addition, both mouse and rat models have deficits in central chemosensitivity or chemoreflexes indicating at least some level of CNS pathology ( 20 , 28 , 29 ). However, it is unclear whether neuronal excitability or seizure susceptibility have been assessed in the Kcnj16 –/– mice.…”

“…Our previous work indicated that the K ir 5.1 mutation in the kidney led to a complex cardiorenal phenotype, including low body weight, renin-angiotensin-aldosterone system dysregulation, hypokalemia, and protection from salt-induced hypertension with dietary K + supplementation ( 18 , 19 ). SS Kcnj16–/– rats also showed deficits in acute (CNS-respiratory) and chronic (renal) acid/base dysregulation ( 20 ). These findings suggest that K ir 5.1 plays a nonredundant role in fundamental physiological homeostasis ( 18 , 19 , 21 – 23 ).…”