Maintaining K+ balance on the low-Na+, high-K+ diet

A low-Na+, high-K+ diet (LNaHK) is considered a healthier alternative to the “Western” high-Na+ diet. Because the mechanism for K+ secretion involves Na+ reabsorptive exchange for secreted K+ in the distal nephron, it is not understood how K+ is eliminated with such low Na+ intake. Animals on a LNaHK diet produce an alkaline load, high urinary flows, and markedly elevated plasma ANG II and aldosterone levels to maintain their K+ balance. Recent studies have revealed a potential mechanism involving the actions of alkalosis, urinary flow, elevated ANG II, and aldosterone on two types of K+ channels, renal outer medullary K+ and large-conductance K+ channels, located in principal and intercalated cells. Here, we review these recent advances.

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Furosemide reduces BK-αβ4-mediated K+ secretion in mice on an alkaline high-K+ diet

AJP Renal Physiology ◽

10.1152/ajprenal.00223.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. F341-F350 ◽

Cited By ~ 4

Author(s):

Bangchen Wang ◽

Jun Wang-France ◽

Huaqing Li ◽

Steven C. Sansom

Keyword(s):

Plasma Aldosterone ◽

Elevated Plasma ◽

Wild Type ◽

Distal Nephron ◽

Urine Ph ◽

Alkaline Urine ◽

High K ◽

K Secretion ◽

Cardioprotective Effects ◽

Apical Localization

Special high-K diets have cardioprotective effects and are often warranted in conjunction with diuretics such as furosemide for treating hypertension. However, it is not understood how a high-K diet (HK) influences the actions of diuretics on renal K+ handling. Furosemide acidifies the urine by increasing acid secretion via the Na+-H+ exchanger 3 (NHE3) in TAL and vacuolar H+-ATPase (V-ATPase) in the distal nephron. We previously found that an alkaline urine is required for large conductance Ca2+-activated K+ (BK)-αβ4-mediated K+ secretion in mice on HK. We therefore hypothesized that furosemide could reduce BK-αβ4-mediated K+ secretion by acidifying the urine. Treating with furosemide (drinking water) for 11 days led to decreased urine pH in both wild-type (WT) and BK-β4-knockout mice (BK-β4-KO) with increased V-ATPase expression and elevated plasma aldosterone levels. However, furosemide decreased renal K+ clearance and elevated plasma [K+] in WT but not BK-β4-KO. Western blotting and immunofluorescence staining showed that furosemide treatment decreased cortical expression of BK-β4 and reduced apical localization of BK-α in connecting tubules. Addition of the carbonic anhydrase inhibitor, acetazolamide, to furosemide water restored urine pH along with renal K+ clearance and plasma [K+] to control levels. Acetazolamide plus furosemide also restored the cortical expression of BK-β4 and BK-α in connecting tubules. These results indicate that in mice adapted to HK, furosemide reduces BK-αβ4-mediated K+ secretion by acidifying the urine.

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Cell-specific regulation of L-WNK1 by dietary K+

AJP Renal Physiology ◽

10.1152/ajprenal.00226.2015 ◽

2016 ◽

Vol 310 (1) ◽

pp. F15-F26 ◽

Cited By ~ 8

Author(s):

Tennille N. Webb ◽

Rolando Carrisoza-Gaytan ◽

Nicolas Montalbetti ◽

Anna Rued ◽

Ankita Roy ◽

...

Keyword(s):

Bk Channels ◽

Bk Channel ◽

Intercalated Cells ◽

Distal Nephron ◽

Α Subunit ◽

High K ◽

Pseudohypoaldosteronism Type Ii ◽

Genes Encoding ◽

Channel Expression ◽

Specific Regulation

Flow-induced K+ secretion in the aldosterone-sensitive distal nephron is mediated by high-conductance Ca2+-activated K+ (BK) channels. Familial hyperkalemic hypertension (pseudohypoaldosteronism type II) is an inherited form of hypertension with decreased K+ secretion and increased Na+ reabsorption. This disorder is linked to mutations in genes encoding with-no-lysine kinase 1 (WNK1), WNK4, and Kelch-like 3/Cullin 3, two components of an E3 ubiquitin ligase complex that degrades WNKs. We examined whether the full-length (or “long”) form of WNK1 (L-WNK1) affected the expression of BK α-subunits in HEK cells. Overexpression of L-WNK1 promoted a significant increase in BK α-subunit whole cell abundance and functional channel expression. BK α-subunit abundance also increased with coexpression of a kinase dead L-WNK1 mutant (K233M) and with kidney-specific WNK1 (KS-WNK1), suggesting that the catalytic activity of L-WNK1 was not required to increase BK expression. We examined whether dietary K+ intake affected L-WNK1 expression in the aldosterone-sensitive distal nephron. We found a paucity of L-WNK1 labeling in cortical collecting ducts (CCDs) from rabbits on a low-K+ diet but observed robust staining for L-WNK1 primarily in intercalated cells when rabbits were fed a high-K+ diet. Our results and previous findings suggest that L-WNK1 exerts different effects on renal K+ secretory channels, inhibiting renal outer medullary K+ channels and activating BK channels. A high-K+ diet induced an increase in L-WNK1 expression selectively in intercalated cells and may contribute to enhanced BK channel expression and K+ secretion in CCDs.

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Bicarbonate promotes BK-α/β4-mediated K excretion in the renal distal nephron

AJP Renal Physiology ◽

10.1152/ajprenal.00490.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. F1563-F1571 ◽

Cited By ~ 18

Author(s):

Ryan J. Cornelius ◽

Donghai Wen ◽

Lori I. Hatcher ◽

Steven C. Sansom

Keyword(s):

Immunohistochemical Analysis ◽

Compensatory Mechanism ◽

Intercalated Cells ◽

Wild Type ◽

Distal Nephron ◽

Acid Base ◽

Urinary Ph ◽

High K ◽

K Secretion ◽

K Concentration

Ca-activated K channels (BK), which are stimulated by high distal nephron flow, are utilized during high-K conditions to remove excess K. Because BK predominantly reside with BK-β4 in acid/base-transporting intercalated cells (IC), we determined whether BK-β4 knockout mice (β4KO) exhibit deficient K excretion when consuming a high-K alkaline diet (HK-alk) vs. high-K chloride diet (HK-Cl). When wild type (WT) were placed on HK-alk, but not HK-Cl, renal BK-β4 expression increased (Western blot). When WT and β4KO were placed on HK-Cl, plasma K concentration ([K]) was elevated compared with control K diets; however, K excretion was not different between WT and β4KO. When HK-alk was consumed, the plasma [K] was lower and K clearance was greater in WT compared with β4KO. The urine was alkaline in mice on HK-alk; however, urinary pH was not different between WT and β4KO. Immunohistochemical analysis of pendrin and V-ATPase revealed the same increases in β-IC, comparing WT and β4KO on HK-alk. We found an amiloride-sensitive reduction in Na excretion in β4KO, compared with WT, on HK-alk, indicating enhanced Na reabsorption as a compensatory mechanism to secrete K. Treating mice with an alkaline, Na-deficient, high-K diet (LNaHK) to minimize Na reabsorption exaggerated the defective K handling of β4KO. When WT on LNaHK were given NH4Cl in the drinking water, K excretion was reduced to the magnitude of β4KO on LNaHK. These results show that WT, but not β4KO, efficiently excretes K on HK-alk but not on HK-Cl and suggest that BK-α/β4-mediated K secretion is promoted by bicarbonaturia.

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Effects of angiotensin II and atrial natriuretic peptide alone and in combination on urinary water and electrolyte excretion in man

Clinical Science ◽

10.1042/cs0740419 ◽

1988 ◽

Vol 74 (4) ◽

pp. 419-425 ◽

Cited By ~ 19

Author(s):

J. McMurray ◽

A. D. Struthers

Keyword(s):

Angiotensin Ii ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Normal Male ◽

Urinary Flow ◽

Ang Ii ◽

Electrolyte Excretion ◽

Water Excretion ◽

Background Infusion ◽

Atrial Natriuretic

1. Atrial natriuretic peptide (ANP) has previously been shown to inhibit the renin–angiotensin–aldosterone system (RAAS) at several different levels. We have now investigated a further non-endocrine, renal interaction between ANP and the RAAS. 2. The effects of ANP and angiotensin II (ANG II) alone, and in combination, on urinary electrolyte and water excretion were studied in eight normal male subjects undergoing maximal water diuresis. 3. ANP caused a significant increase in urine flow and sodium excretion. ANG II alone was antidiuretic, antinatriuretic and antikaliuretic. When ANP was given against a background infusion of ANG II, urinary flow rate and electrolyte excretion increased from a new lower level to reach a value intermediate between that found with ANG II alone and ANP alone. 4. It is concluded that the renal effects of ANP are modified in the presence of simultaneously elevated levels of ANG II and that net water and electrolyte excretion reflect the sum of the opposing influences of each peptide. While this interplay may be non-specific, it is possible that ANP may exert some of its actions by specifically inhibiting the intrarenal effects of ANG II.

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Abstract P173: Role Of Potassium Intake On Hypertensive Cardiovascular Damage In Apolipoproteine-deficient Mice Under Normal And High Salt Conditions

Hypertension ◽

10.1161/hyp.76.suppl_1.p173 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Mina Yakoub ◽

Denada Arifaj ◽

Doron Argov ◽

Masudur Rahman ◽

Sebastian Temme ◽

...

Keyword(s):

Blood Pressure ◽

Cardiac Hypertrophy ◽

Aortic Arch ◽

High Salt ◽

Ang Ii ◽

Cardiac Damage ◽

High Sodium ◽

Cardiovascular Damage ◽

High K ◽

Deficient Mice

Reduced potassium (k+) intake has been linked to cardiovascular diseases. The underlying mechanisms remain unknown. Here, we investigate the effect of low (0%), normal (0.5%) and high K+ (5%) diet on the development of atherosclerosis and hypertensive cardiac damage. To induce atherosclerosis, apolipoprotein-deficient mice were infused with angiotensin (Ang) II (500ng/kg/min) for 28 days. Potassium treatment was initiated 2 weeks before Ang II infusion. Cardiac function was assessed by MRI. Levels of K+ in the serum and urine were significantly different between groups. The Ang II infused mice from the K+ low group had significantly higher atherosclerotic plaques in the aortic arch (21±3%) compared to K+ high (10±2%) and K+ normal (11±2%) groups. The atherosclerosis development was blood pressure independent since no differences in blood pressure between the groups were observed. Although heart to body-weight ratio did not differ between three groups, K+ low diet was associated with a lower ejection fraction rate and increased mRNA expression levels of cardiac ANP, BNP, collagen and fibronectin compared to the K+ normal and K+ high group. After Ang II infusion, assessment of aldosterone levels in urine showed significant higher aldosterone levels in the high K+ (214±72ng/24h) compared to normal K+ (26±6ng/24h) and low K+ (18±4ng/24h) groups. Aldosterone induced cardiovascular damage is known to be aggravated by sodium. To, evaluate whether high sodium diet unmask aldosterone mediated cardiovascular damage in the high K+ group, mice fed a high or normal K+ diet were additionally treated with high sodium (1% NaCl) in the drinking water. During Ang II treatment, high salt diet accelerated atherosclerosis in the aortic arch of both groups but no differences were observed between the high K+ high/high Na+ (41±7%) and normal K+/high Na+ (49±2%) group. In contrast, high K+/high Na+ group have significantly more severe cardiac hypertrophy compared to normal K+ high Na+ group (8.9±0.7 vs 6.4±0.7mg/g). These results were confirmed by MRI. K+ deficient diet induces atherosclerosis and cardiac damage during Ang II induced hypertension. K+ enriched diet exacerbates cardiac hypertrophy only under high Na+ conditions most likely in an aldosterone-dependent mechanism.

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Potassium secretion and the regulation of distal nephron K channels

AJP Renal Physiology ◽

10.1152/ajprenal.1999.277.6.f821 ◽

1999 ◽

Vol 277 (6) ◽

pp. F821-F825 ◽

Cited By ~ 30

Author(s):

Lawrence G. Palmer

Keyword(s):

Regulatory Process ◽

Distal Nephron ◽

K Channels ◽

Nephron Segments ◽

High K ◽

Potassium Secretion ◽

K Transport

K-selective channels in the luminal membranes of distal nephron segments form a key pathway for the secretion of K ions into the urine. This process is important to the control of K balance, particularly under conditions of normal or high K intake. This brief review will cover three issues: 1) the identification of apical K channels, 2) the role of these channels in the maintenance of K homeostasis, and 3) the role of aldosterone in this regulatory process. The large amount of literature on renal K transport has been elegantly summarized in a recent review in this journal [G. Giebisch. Am. J. Physiol.274 ( Renal Physiol. 43): F817–F833, 1998]. Here I will focus on a few prominent unsolved problems.

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RVD in principal and intercalated cells of rabbit cortical collecting tubule

AJP Cell Physiology ◽

10.1152/ajpcell.1988.255.5.c612 ◽

1988 ◽

Vol 255 (5) ◽

pp. C612-C621 ◽

Cited By ~ 21

Author(s):

K. Strange

Keyword(s):

Mammalian Cells ◽

Control Volume ◽

Regulatory Volume Decrease ◽

Isotonic Saline ◽

Cell Types ◽

Intercalated Cells ◽

Intercalated Cell ◽

Collecting Tubule ◽

Principal And Intercalated Cells ◽

Cortical Collecting Tubule

Cells of the rabbit renal cortical collecting tubule possess significant regulatory volume decrease (RVD) capabilities. After a 100-mosmol/kg reduction in peritubular osmolality, principal and intercalated cells swell 40-45 and 30-35%, respectively, and immediately activate RVD mechanisms. Both cell types downregulate their volume to within 5-6% of control volume at initial rates of 3-6%/min. Return to isotonic saline causes both cell types to shrink (isotonic shrinkage) 25-35% below control volume due to the loss of osmotically active intracellular solutes during RVD. In most mammalian cells studied to date, RVD is mediated largely by passive KCl efflux via KCl cotransport, parallel K+ and Cl- channels, or parallel K+-H+ and Cl- -HCO3- exchange mechanisms. Peritubular application of 0.1 mM ouabain (0 Na+ lumen), bilateral CO2-HCO3- removal, or bilateral application of 0.02 mM bumetanide, 2.0 mM Ba2+, 2.0 mM anthracene-9-carboxylic acid, or 0.5 mM SITS had no significant effect on rates or magnitudes of RVD and isotonic shrinkage in either cell type. Bilateral elevation of K+ from 5 to 52.5 mM reverses or reduces the electrochemical gradient for K+ movement, causing accumulation of this ion in the cytoplasm, but had no effect on the rates or magnitude of principal and intercalated cell RVD. Principal and intercalated cells from K+- or Cl- -depleted tubules (1 h bilateral perfusion with K+- or Cl- -free saline at 37 degrees C) showed normal rates and magnitudes of RVD in K+- or Cl- -free hypotonic saline. Taken together, these results argue against a significant role of passive KCl efflux pathways in mediating principal and intercalated cell RVD.

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Minealocorticoid receptors and 11 beta-steroid dehydrogenase activity in renal principal and intercalated cells

AJP Renal Physiology ◽

10.1152/ajprenal.1994.266.1.f76 ◽

1994 ◽

Vol 266 (1) ◽

pp. F76-F80 ◽

Cited By ~ 8

Author(s):

A. Naray-Fejes-Toth ◽

E. Rusvai ◽

G. Fejes-Toth

Keyword(s):

Cell Sorting ◽

Direct Action ◽

Collecting Duct ◽

Cell Types ◽

Target Cells ◽

Intercalated Cells ◽

Cortical Collecting Duct ◽

Specific Receptors ◽

Principal And Intercalated Cells ◽

Steroid Dehydrogenase

Aldosterone exerts complex effects on the cortical collecting duct (CCD): it increases Na+ and K+ transport, and it also influences H+ and HCO3 transport. Whether these latter effects represent direct action of aldosterone on intercalated cells (ICC) or are secondary to changes in the transport of other electrolytes is unclear. Because the presence of specific receptors is the prerequisite of a direct steroid action, and mineralocorticoid receptors (MR) have not yet been demonstrated in ICC, in this study we determined the density of MR directly in isolated principal cells (PC) and beta-ICC. Purified populations of these two cell types were obtained from rabbit renal cortex by immunodissection and fluorescence-activated cell sorting. We found that both PC and beta-ICC contained a significant number of MR, although receptor density was higher in PC than in beta-ICC (6,704 +/- 912 vs. 2,181 +/- 388 MR sites/cell; P < 0.001). 11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD), an enzyme that is present predominantly in mineralocorticoid target cells, exhibited a distribution similar to that of MR in the two cell types. 11 beta-OHSD activity, determined by measuring the rate of conversion of [3H]corticosterone to 11-dehydrocorticosterone, was 1.08 +/- 0.14 and 0.34 +/- 0.08 fmol.min-1 x 1,000 cells-1 (P < 0.001) in intact PC and beta-ICC, respectively. 11 beta-OHSD in both cell types utilized NAD as cofactor. These results suggest that beta-ICC are potential direct targets of aldosterone and that MR in both PC and beta-ICC are protected by 11 beta-OHSD.

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A fate-mapping approach reveals the composite origin of the connecting tubule and alerts on “single-cell”-specific KO model of the distal nephron

AJP Renal Physiology ◽

10.1152/ajprenal.00286.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. F901-F906 ◽

Cited By ~ 22

Author(s):

Francesco Trepiccione ◽

Christelle Soukaseum ◽

Anna Iervolino ◽

Federica Petrillo ◽

Miriam Zacchia ◽

...

Keyword(s):

Single Cell ◽

Kidney Development ◽

Fluorescent Protein ◽

Collecting Duct ◽

Yellow Fluorescent Protein ◽

Cell Types ◽

Intercalated Cells ◽

Distal Nephron ◽

Principal Cells ◽

Different Cell Types

The distal nephron is a heterogeneous part of the nephron composed by six different cell types, forming the epithelium of the distal convoluted (DCT), connecting, and collecting duct. To dissect the function of these cells, knockout models specific for their unique cell marker have been created. However, since this part of the nephron develops at the border between the ureteric bud and the metanephric mesenchyme, the specificity of the single cell markers has been recently questioned. Here, by mapping the fate of the aquaporin 2 (AQP2) and Na+-Cl−cotransporter (NCC)-positive cells using transgenic mouse lines expressing the yellow fluorescent protein fluorescent marker, we showed that the origin of the distal nephron is extremely composite. Indeed, AQP2-expressing precursor results give rise not only to the principal cells, but also to some of the A- and B-type intercalated cells and even to cells of the DCT. On the other hand, some principal cells and B-type intercalated cells can develop from NCC-expressing precursors. In conclusion, these results demonstrate that the origin of different cell types in the distal nephron is not as clearly defined as originally thought. Importantly, they highlight the fact that knocking out a gene encoding for a selective functional marker in the adult does not guarantee cell specificity during the overall kidney development. Tools allowing not only cell-specific but also time-controlled recombination will be useful in this sense.

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Mechanisms of the antinatriuretic action of physiological doses of angiotensin II in man

Clinical Science ◽

10.1042/cs0760653 ◽

1989 ◽

Vol 76 (6) ◽

pp. 653-658 ◽

Cited By ~ 13

Author(s):

Peter H. Seidelin ◽

John J. McMurray ◽

Allan D. Struthers

Keyword(s):

Creatinine Clearance ◽

Sodium Excretion ◽

Free Water ◽

Sodium Reabsorption ◽

Ang Ii ◽

Distal Nephron ◽

Aldosterone Secretion ◽

Significant Fall ◽

Parallel Change ◽

Proximal Tubular

1. Angiotensin 11 (ANG II; 1 ng min−1 kg−1) or 5% (w/v) d-glucose (placebo) was infused in six normal male volunteers, pretreated with 500 mg of lithium carbonate, who were undergoing maximal water diuresis. 2. This dose of ANG II caused a circulating increment within the physiological range (27 ± 4 to 48 ± 9 pmol/l). 3. Compared with placebo, ANG II caused a significant fall in urinary sodium excretion (113 ± 13 to 82 ± 10 μmol/min). This antinatriuretic effect occurred without a fall in creatinine clearance (107 ± 3 versus 113 ± 3 ml/min). 4. ANG II caused a significant fall in fractional lithium clearance (28 ± 2 to 23 ± 2%). This may indicate a proximal tubular effect of ANG II. 5. ANG II also reduced fractional distal delivery [(sodium clearance plus free water clearance) divided by creatinine clearance], another measure of proximal tubular outflow. A parallel change in these two separate markers of proximal function supports an action of ANG II at this nephron segment. 6. Furthermore, the antinatriuretic effect of ANG II was unlikely to be due to stimulation of aldosterone secretion because (a) the fall in sodium excretion was temporally dissociated from the rise in aldosterone secretion, (b) potassium excretion also tended to fall during ANG II infusion and (c) aldosterone has a distal nephron effect, while, in this study, proximal nephron fractional reabsorption of sodium increased and distal nephron fractional reabsorption of sodium was unchanged. 7. These observations suggest that physiological increments in ANG II can have an antinatriuretic effect in man, which, at least initially, results from increased proximal tubular sodium reabsorption and is independent of the effect of aldosterone.

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