Interplay between Kir4.1/Kir5.1 channels, RAAS and electrolyte balance

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Abstract: Enhanced sensitivity of blood pressure to salt intake is present in nearly half of Americans afflicted with hypertension, including approximately 75% of African American hypertensive patients. The effect of sodium on blood pressure is dependent on diet composition, specifically on the Na+/K+ ratio. Diets supplemented with high K+ are associated with a lower risk of major cardiovascular events. Despite highly relevant clinical and translational evidence supporting the benefits of a high-potassium diet, there is a substantial lack in our understanding of the underlying molecular mechanisms. Ion channels and transporters in the aldosterone- sensitive distal nephron (ASDN) determine the transport rate and the subsequent urinary excretion of electrolytes, including Na+ and K+. Inwardly rectifying K+ (Kir) channels, specifically Kir4.1/Kir5.1 (encoded by Kcnj10 and Kcnj16 genes, respectively), are the major basolateral K+ channels in the ASDN and play an important role in precisely maintaining electrolyte homeostasis in the kidney. 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. 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 as well as ENaC inhibition with benzamil treatment prevented salt-induced death. However, specific mechanisms pertaining to the 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. In addition to SSKcnj16-/- rats, we have created an SSKcnj10-/- model in which Kir4.1 (Kcnj10) has also been knocked out in the SS rat; these two models enable us to assess the role of Kir4.1/Kir5.1 (Kcnj10/Kcnj16) channels in blood pressure control and renal function. Given the reported associations of Kcnj10/Kcnj16 with a variety of cardiorenal diseases in humans, it is important to understand the mechanisms by which Kir4.1/Kir5.1 can influence electrolyte homeostasis, the activity of other channels and transporters, and blood pressure control in the context of salt- induced hypertension. Additionally, the capacity of Kir4.1/Kir5.1 channel activity to influence the RAAS, another major controller of blood pressure, requires investigation. I hypothesize that the activity of Kir4.1/Kir5.1 channels in the distal nephron is a major determinant of blood pressure through influencing the RAAS as well as electrolyte balance by modulating ion channels and transporters in ASDN. There are two specific aims which will address the proposed hypothesis: 1) To determine the influence of dysfunctional renal Kir4.1/Kir5.1 channels on ion channels in the ASDN and on whole body electrolyte homeostasis; 2) To define the mechanistic link between renal Kir4.1/Kir5.1 channels and RAAS and the implications of this interaction for blood pressure control.