TY - JOUR
T1 - Essential role of Kir5.1 channels in renal salt handling and blood pressure control
AU - Palygin, Oleg
AU - Levchenko, Vladislav
AU - Ilatovskaya, Daria V.
AU - Pavlov, Tengis S.
AU - Pochynyuk, Oleh M.
AU - Jacob, Howard J.
AU - Geurts, Aron M.
AU - Hodges, Matthew R.
AU - Staruschenko, Alexander
N1 - Funding Information:
We would like to thank Jessica L. Barnett, Oleh Prudnikov, Christine Nguyen, Jennifer M Connell, and Chun Yang for experimental help and analysis; Paula North and Christine Duris for histology and immunohistochemistry experiments and their interpretation; David L. Mattson, Lisa Henderson, and Camille Torres for help with biochemical assays; and Andrey Ilatovskiy for development of software used in GFR measurements. David H. Ellison (Oregon Health & Science University, Portland) and Pablo Ortiz (Henry Ford Hospital, Detroit) are greatly appreciated for providing antibodies. This research was supported by the NIH grants HL135749, HL10880, HL122662 (to A.S.), HL122358 (to M.H.), HL101681 (to H.J. and A.G.), OD008396 (A.G.); MCW NRC/AHW pilot grant 9520217 (to O. Palygin and M.H.); and American Heart Association grants 16EIA26720006 (to A.S.) and 17SDG33660149 (to O. Palygin).
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/9/21
Y1 - 2017/9/21
N2 - Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels Kir4.1 (Kcnj10) and Kir5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na+ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of Kir5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SSKcnj16–/–). SSKcnj16–/– rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia. Electrophysiological recordings of basolateral K+ channels in the collecting ducts isolated from SSKcnj16–/– rats revealed activity of only homomeric Kir4.1 channels. Kir4.1 expression was upregulated in SSKcnj16–/– rats, but the protein was predominantly localized in the cytosol in SSKcnj16–/– rats. Benzamil, but not hydrochlorothiazide or furosemide, rescued this phenotype from mortality on a high-salt diet. Supplementation of high-salt diet with increased potassium (2% KCl) prevented mortality in SSKcnj16–/– rats and prevented or mitigated hypertension in SSKcnj16–/– or control SS rats, respectively. Our results demonstrate that Kir5.1 channels are key regulators of renal salt handling in SS hypertension.
AB - Supplementing diets with high potassium helps reduce hypertension in humans. Inwardly rectifying K+ channels Kir4.1 (Kcnj10) and Kir5.1 (Kcnj16) are highly expressed in the basolateral membrane of distal renal tubules and contribute to Na+ reabsorption and K+ secretion through the direct control of transepithelial voltage. To define the importance of Kir5.1 in blood pressure control under conditions of salt-induced hypertension, we generated a Kcnj16 knockout in Dahl salt-sensitive (SS) rats (SSKcnj16–/–). SSKcnj16–/– rats exhibited hypokalemia and reduced blood pressure, and when fed a high-salt diet (4% NaCl), experienced 100% mortality within a few days triggered by salt wasting and severe hypokalemia. Electrophysiological recordings of basolateral K+ channels in the collecting ducts isolated from SSKcnj16–/– rats revealed activity of only homomeric Kir4.1 channels. Kir4.1 expression was upregulated in SSKcnj16–/– rats, but the protein was predominantly localized in the cytosol in SSKcnj16–/– rats. Benzamil, but not hydrochlorothiazide or furosemide, rescued this phenotype from mortality on a high-salt diet. Supplementation of high-salt diet with increased potassium (2% KCl) prevented mortality in SSKcnj16–/– rats and prevented or mitigated hypertension in SSKcnj16–/– or control SS rats, respectively. Our results demonstrate that Kir5.1 channels are key regulators of renal salt handling in SS hypertension.
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UR - http://www.scopus.com/inward/citedby.url?scp=85049388582&partnerID=8YFLogxK
U2 - 10.1172/JCI.INSIGHT.92331
DO - 10.1172/JCI.INSIGHT.92331
M3 - Article
C2 - 28931751
AN - SCOPUS:85049388582
VL - 2
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 18
M1 - e92331
ER -