TY - JOUR
T1 - Interacting influence of diuretics and diet on BK channel-regulated K homeostasis
AU - Wen, Donghai
AU - Cornelius, Ryan J.
AU - Sansom, Steven C.
PY - 2014/4
Y1 - 2014/4
N2 - Large conductance, Ca-activated K channels (BK) are abundantly located in cells of vasculature, glomerulus, and distal nephron, where they are involved in maintaining blood volume, blood pressure, and K homeostasis. In mesangial cells and smooth muscle cells of vessels, the BK-α pore associates with BK-β1 subunits and regulates contraction in a Ca-mediated feedback manner. The BK-β1 also resides in connecting tubule cells of the nephron. BK-β1 knockout mice (β1KO) exhibit fluid retention, hypertension, and compromised K handling. The BK-α/β4 resides in acid/base transporting intercalated cells (IC) of the distal nephron, where they mediate K secretion in mammals on a high K, alkaline diet. BK-α expression in IC is increased by a high K diet via aldosterone. The BK-β4 subunit and alkaline urine are necessary for the luminal expression and function of BK-α in mouse IC. In distal nephron cells, membrane BK-α expression is inhibited by WNK4 in in vitro expression systems, indicating a role in the hyperkalemic phenotype in patients with familial hyperkalemic hypertension type 2 (FHHt2). β1KO and BK-β4 knockout mice (β4KO) are hypertensive because of exaggerated epithelial Na channels (ENaC) mediated Na retention in an effort to secrete K via only renal outer medullary K channels (ROMK). BK hypertension is resistant to thiazides and furosemide, and would be more amenable to ENaC and aldosterone inhibiting drugs. Activators of BK-α/β1 or BK-α/β4 might be effective blood pressure lowering agents for a subset of hypertensive patients. Inhibitors of renal BK would effectively spare K in patients with Bartter Syndrome, a renal K wasting disease.
AB - Large conductance, Ca-activated K channels (BK) are abundantly located in cells of vasculature, glomerulus, and distal nephron, where they are involved in maintaining blood volume, blood pressure, and K homeostasis. In mesangial cells and smooth muscle cells of vessels, the BK-α pore associates with BK-β1 subunits and regulates contraction in a Ca-mediated feedback manner. The BK-β1 also resides in connecting tubule cells of the nephron. BK-β1 knockout mice (β1KO) exhibit fluid retention, hypertension, and compromised K handling. The BK-α/β4 resides in acid/base transporting intercalated cells (IC) of the distal nephron, where they mediate K secretion in mammals on a high K, alkaline diet. BK-α expression in IC is increased by a high K diet via aldosterone. The BK-β4 subunit and alkaline urine are necessary for the luminal expression and function of BK-α in mouse IC. In distal nephron cells, membrane BK-α expression is inhibited by WNK4 in in vitro expression systems, indicating a role in the hyperkalemic phenotype in patients with familial hyperkalemic hypertension type 2 (FHHt2). β1KO and BK-β4 knockout mice (β4KO) are hypertensive because of exaggerated epithelial Na channels (ENaC) mediated Na retention in an effort to secrete K via only renal outer medullary K channels (ROMK). BK hypertension is resistant to thiazides and furosemide, and would be more amenable to ENaC and aldosterone inhibiting drugs. Activators of BK-α/β1 or BK-α/β4 might be effective blood pressure lowering agents for a subset of hypertensive patients. Inhibitors of renal BK would effectively spare K in patients with Bartter Syndrome, a renal K wasting disease.
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U2 - 10.1016/j.coph.2013.11.001
DO - 10.1016/j.coph.2013.11.001
M3 - Review article
C2 - 24721651
AN - SCOPUS:84889870474
SN - 1471-4892
VL - 15
SP - 28
EP - 32
JO - Current Opinion in Pharmacology
JF - Current Opinion in Pharmacology
IS - 1
ER -