Relationship between the renin–angiotensin–aldosterone system and renal Kir5.1 channels

Abstract

Kir5.1 (encoded by the Kcnj16 gene) is an inwardly rectifying K+ (Kir) channel highly expressed in the aldosterone-sensitive distal nephron of the kidney, where it forms a functional channel with Kir4.1. Kir4.1/Kir5.1 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 ir4.1/Kir5.1-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 Kir5.1 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 Kir5.1 as a key regulator of the RAAS, particularly when exposed to changes in dietary sodium and potassium content.

Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis

“…Basolateral K + channels in the aldosterone-sensitive distal nephron (ASDN), including the distal convoluted tubule (DCT) and the cortical collecting duct, are essential for controlling basolateral membrane potential and in recycling of K + taken up into the cell by the basolateral Na-K-ATPase, the ubiquitous pump that drives transepithelial Na + absorption [ 1 ]. KCNJ16 encodes K ir 5.1, which itself does not conduct K + , but which forms a heterotetramer with K ir 4.1, encoded by KCNJ10 [ 2 ]. The K ir 4.1/K ir 5.1 channel, the predominant basolateral K + channel in ASDN, is an inwardly rectifying potassium channel that is exquisitely sensitive to intracellular pH within the physiological range.…”

“…These rats also exhibit hyperventilation at rest in response to chronic hyperchloremic metabolic acidosis [ 5 ]. Aldosterone and angiotensin peptides are increased in SS Kcnj16 −/ − rats compared to SS WT rats, and these rats have an altered renin–angiotensin–aldosterone system response to high-salt and high-K + diets [ 2 ].…”

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

“…Patients with drug-resistant (refractory) epilepsies are faced with diminished quality of life and a 24-fold increased risk of spontaneous seizure-related mortality (19). Sudden Unexpected Death in Epilepsy (SUDEP) represents a major cause of death in this patient cohort and affects patients of all ages (31).…”

“…SS Kcnj16-/rats also showed deficits in acute (CNS-respiratory) and chronic (renal) acid/base dysregulation (20). These findings suggest that Kir5.1 plays a non-redundant role in fundamental physiological homeostasis (18,19,(21)(22)(23). Given that Kir5.1 is highly expressed in the CNS, loss of Kir5.1 expression may destabilize the resting membrane potential, thereby altering neuronal excitability and resulting in additional neurological phenotypes.…”

“…To investigate the neurological, physiological, and pathophysiological role of Kir5.1, we utilized a recently generated and validated global knockout of Kcnj16 (SS Kcnj16-/rats) on the Dahl Salt-Sensitive (SS) rat background (18). Our previous work described that the Kir5.1 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).…”