Role of BK-alpha 1 in flow-dependent K secretion in the CNT

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Large conductance, Ca-activated K channels (BK) are comprised of a pore-forming alpha subunit (BK-α) and an ancillary beta subunit (BK-ß1-4). BK hypertension, demonstrated by several laboratories for mice with knock-outs of the BK-ß1 subunit (ß1KO), is mostly the result of fluid retention secondary to defective renal handling of K resulting in hyperkalemic aldosteronism. This competitive renewal proposes to continue studies of the regulation of the renal BK-α/ß1. We previously determined with ß1KO and ß4KO that BK-α/ß1 and BK-α/ß4, which are localized in the connecting tubule principal cells (CNT) and intercalated cells (IC), respectively, of the distal nephron, have distinct roles to maximize the K secreted per Na reabsorbed when animals are placed on a high K diet. The first Aim determines the relative roles of aldosterone and high plasma [K] to enhance BK-α/ß1 mediated K secretion. The second Aim addresses the role of BK-α/ß1 in Na-independent K secretion. When mice are placed on a low Na diet, the transtubular K gradient (TTKG), an indirect measurement of the driving force for K secretion, is significantly reduced for ß1KO, compared with WT. These data indicate that the BK-α/ß1 is used for non-ENaC-mediated, Na-independent K secretion. We have preliminary evidence that the large negative transepithelial potential required for Na-independent K secretion is the result of ß-IC cell HCO3 secretion via pendrin in conjunction with apical Cl recycling via CFTR Cl channels. The third Aim is based on our previous study showing co-dependent transport of K and ATP from IC cells of the cortical collecting duct. This Aim will examine the role of the BK-α/ß4 in IC to enhance the ratio of K secreted to Na absorbed in the CNT and cortical collecting ducts by the high flow-induced excretion of ATP, which locally inhibits ENaC-mediated Na reabsorption. These results will be important for determining how K is handled by renal BK channels in conditions of iatrogenic increases in plasma [K] or with crush syndrome, which causes fatal increases in plasma [K] levels.