Kir5.1‐Mediated Changes in Renin‐Angiotensin‐Aldosterone System Balance in Salt Sensitive Hypertension

Abstract

Kir5.1 (encoded by Kcnj16 gene) is a member of the inwardly rectifying K+ channel (Kir) family which is expressed in the kidney where it plays an essential role in the maintenance of electrolyte balance and blood pressure control. More specifically, Kir5.1 is highly expressed in the distal convoluted tubule and collecting ducts, also known as the aldosterone‐sensitive distal nephron (ASDN), where it forms a functional channel with Kir4.1. Our previous studies revealed that a knockout of Kcnj16 in the Dahl salt‐sensitive rat (SSKcnj16−/−) results in decreased blood pressure, salt wasting tubulopathy, and hypokalemia (Palygin et al., JCI Insight, 2017). Furthermore, when fed a high salt diet (HS; 4% NaCl), hypokalemia was exacerbated and resulted in mortality of SSKcnj16−/− rats within a few days. Importantly, dietary potassium supplementation or ENaC inhibition with benzamil treatment prevented salt‐induced death. However, specific mechanisms pertaining to cardiorenal abnormalities in SSKcnj16−/− rats and the interaction of Kir4.1/Kir5.1‐mediated potassium transport with the renin‐angiotensin‐aldosterone system (RAAS, a major hormone system that controls fluid and electrolyte balance in ASDN) remains unclear. The main objective of this study was to assess the contribution of RAAS, and specifically aldosterone, in the phenotype observed in SSKcnj16−/− rats. We used mass spectrometry‐based quantification of individual RAAS components to examine whether RAAS hormones were altered in SSKcnj16−/− rats. We found that SSKcnj16−/− rats have drastically elevated serum aldosterone (1878 ± 303 pM for SSKcnj16−/− rats vs 183 ± 35 pM for SS control rats) which becomes significantly attenuated preceding mortality upon introduction of a high salt diet (394 ± 82 pM). All angiotensin derivatives were similarly elevated in SSKcnj16−/− rats, as were RAAS hormone ratios as surrogate measures of angiotensin‐converting enzyme (ACE) activity (Ang II/Ang I), plasma renin activity (PRA, Ang I+Ang II), and primary aldosteronism (AA2‐Ratio). No significant differences in circulating RAAS hormones between male and female rats were observed. Furthermore, blocking aldosterone action with the administration of the potassium‐sparing diuretic, spironolactone (50 mg/kg IP), which is a potent mineralocorticoid receptor antagonist, did not prevent mortalities from a HS diet. Moreover, spironolactone caused 100% mortality within 48 hrs in SSKcnj16−/− (N = 17) but not SS rats during low salt treatment. Blood electrolyte analysis after 24 hrs treatment with spironolactone did not indicate a decline in serum potassium, which was the cause of mortality due to HS intake. Despite this, dietary potassium supplementation (0.36% to 1.41% dietary K+) prevented mortalities due to spironolactone administration in SSKcnj16−/− rats (N = 6). Our data suggest that there is a direct correlation between Kir4.1/Kir5.1‐mediated potassium transport and RAAS function. Our current studies further reveal that hypokalemia due to Kir5.1 deletion results in compensatory RAAS elevation and that supplementation of the diet with high K+ protects from mortality resulting from aldosteronemediated mechanisms.Support or Funding InformationNIHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.