Abstract P013: Role Of Kir4.1 ( Kcnj10 ) In The Regulation Of Salt-Induced Hypertension

Abstract

In the kidney, K ir 4.1 ( Kcnj10 ) and K ir 5.1 ( Kcnj16 ) are highly expressed in the aldosterone sensitive distal nephron, a major target for hormones controlling blood pressure. These basolateral inwardly rectifying potassium channel subunits assemble to form both heteromeric K ir 4.1/K ir 5.1 and homomeric K ir 4.1 channels which control the transepithelial voltage, fine-tune renal electrolyte homeostasis, and contribute to long-term blood pressure control. To study the role of K ir 4.1 in the renal control of blood pressure, renin-angiotensin-aldosterone system (RAAS) balance, and salt-sensitive hypertension, we created a Kcnj10 knockout (SS Kcnj10-/- ) on the Dahl SS rat background using CRISPR/Cas9 mutagenesis. Homozygous SS Kcnj10-/- rats were hypokalemic, had reduced heart, kidney, and body weights, and did not survive more than 3 weeks from birth. Mass spectrometry-based quantification of RAAS peptides revealed increased Ang I, Ang 1-5, and Ang 1-7 levels in SS Kcnj10-/- rats compared to age-matched SS Kcnj10+/+ controls. There were no differences in Ang II, Ang III, Ang IV, or aldosterone levels. In addition, ACE activity was decreased in SS Kcnj10-/- rats. The observed increases in alternative RAS axis peptides and decrease in ACE activity in SS Kcnj10-/- rats are suggestive of a low blood pressure phenotype, however, limited survival precluded blood pressure measurement. Heterozygous (SS Kcnj10+/- ) rats developed normally and showed no changes in serum electrolytes. Survival rate of SS Kcnj10+/- rats was lower than wild-type rats but improved with dietary K + supplementation (1.41% K + ) allowing for telemetric blood pressure measurement. We found no differences in baseline blood pressure under control conditions, but salt-induced (4% NaCl) elevations in blood pressure were significantly attenuated in SS Kcnj10+/- rats. After 3 weeks on high salt, SS Kcnj10+/- rats showed decreased diuresis and improved albuminuria compared to wildtype. Our results demonstrate that renal K ir 4.1 containing channels mediate salt-sensitive increases in blood pressure through regulation of potassium homeostasis, modulation of alternative RAS axis hormones, and control of renal salt handling in the ASDN.