Essential role of Kir5.1 channels in renal salt handling and blood pressure control
Oleg Palygin, Vladislav Levchenko, Daria V. Ilatovskaya, Tengis S. Pavlov, Oleh M. Pochynyuk, Howard J. Jacob, Aron M. Geurts, Matthew R. Hodges, Alexander Staruschenko
Oleg Palygin, Vladislav Levchenko, Daria V. Ilatovskaya, Tengis S. Pavlov, Oleh M. Pochynyuk, Howard J. Jacob, Aron M. Geurts, Matthew R. Hodges, Alexander Staruschenko
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Research Article Nephrology

Essential role of Kir5.1 channels in renal salt handling and blood pressure control

Abstract

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.

Authors

Oleg Palygin, Vladislav Levchenko, Daria V. Ilatovskaya, Tengis S. Pavlov, Oleh M. Pochynyuk, Howard J. Jacob, Aron M. Geurts, Matthew R. Hodges, Alexander Staruschenko

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Figure 7

The combination of a high-potassium diet and Kir5.1 channel deletion mediate the protective effects on the development of SS hypertension.

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The combination of a high-potassium diet and Kir5.1 channel deletion med...
(A) Mean arterial pressure (MAP) in salt-sensitive (SS) and SSKcnj16–/– rats. Blood pressure was measured with radiotelemetry (see also Supplemental Figure 3 for circadian rhythms and heart rate analyses). Animals were switched from a 0.4% to a 4% NaCl diet at day 0. Then, SS rats were fed either a standard 4% NaCl diet (black, N = 10 rats) or a 4% NaCl diet supplemented with high K+ (2% KCl; red, N = 14). SSKcnj16–/– rats were fed a 4% NaCl diet supplemented with high K+ (green, N = 8). Comparisons between groups were made using repeated-measures ANOVA. * P < 0.05 versus SS rats fed a low-K+ diet. (B) Development of albuminuria (albumin to creatinine ratio) in the same groups of animals (N ≥ 8 rats). (C) Urinary electrolyte analysis of rats used in the experimental protocol shown in A; bars indicate electrolyte concentrations in control (0.4% NaCl [LS] or before diet change) and at the end of the experiment (4% NaCl [HS] and with or without K+ supplement) for all groups of animals (N = 8–13 rats in each group; see also Supplemental Figure 4). Comparisons between groups were made using 1-way ANOVA. * P < 0.05 versus SS rats fed a 0.4% NaCl diet.