scholarly journals Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis

2021 ◽  
Author(s):  
Bryn D. Webb ◽  
Hilary Hotchkiss ◽  
Pankaj Prasun ◽  
Bruce D. Gelb ◽  
Lisa Satlin
Keyword(s):  
Metabolic Acidosis ◽  
Membrane Potential ◽  
Basolateral Membrane ◽  
Loss Of Function ◽  
Distal Nephron ◽  
Chronic Metabolic Acidosis ◽  
Whole Exome ◽  
Hyperchloremic Metabolic Acidosis ◽  
Inwardly Rectifying ◽  
Basolateral Membrane Potential

AbstractKCNJ16 encodes Kir5.1 and acts in combination with Kir4.1, encoded by KCNJ10, to form an inwardly rectifying K+ channel expressed at the basolateral membrane of epithelial cells in the distal nephron. This Kir4.1/Kir5.1 channel is critical for controlling basolateral membrane potential and K+ recycling, the latter coupled to Na-K-ATPase activity, which determines renal Na+ handling. Previous work has shown that Kcnj16−/− mice and SSKcnj16−/− rats demonstrate hypokalemic, hyperchloremic metabolic acidosis. Here, we present the first report of a patient identified to have biallelic loss-of-function variants in KCNJ16 by whole exome sequencing who presented with chronic metabolic acidosis with exacerbations triggered by minor infections.

Basolateral membrane H-OH-HCO3 transport in the proximal tubule

1989 ◽  
Vol 256 (5) ◽  
pp. F751-F765
Author(s):  
P. A. Preisig ◽  
R. J. Alpern
Keyword(s):  
Metabolic Acidosis ◽  
Proximal Tubule ◽  
Basolateral Membrane ◽  
Respiratory Acidosis ◽  
Cell Voltage ◽  
Transport Mechanisms ◽  
Transport Capacity ◽  
Chronic Metabolic Acidosis

This review focuses on the basolateral membrane mechanisms of H-OH-HCO3 transport in the proximal tubule. The mechanism that has the greatest transport capacity and mediates most of transepithelial H-HCO3 transport is the electrogenic, Na-3HCO3 cotransporter. This transporter has been extensively characterized in the salamander, rat, and rabbit proximal tubule, and has now been found in a number of other epithelia that effect transepithelial NaHCO3 transport. Transporter rate is sensitive to intra- and extracellular [Na], intra- and extracellular [HCO3]/pH, and cell voltage. Adaptations in transporter activity have been demonstrated in chronic metabolic acidosis and alkalosis, chronic respiratory acidosis and alkalosis, and chronic hyperfiltration. In addition to the Na-3HCO3 cotransporter, the basolateral membrane possesses both Na-dependent and -independent Cl-HCO3 exchangers, a H leak, and in the S3 proximal tubule an Na-H antiporter. The role of these H-OH-HCO3 transport mechanisms in transcellular HCO3 and Cl absorption and pHi defense is discussed.

Adaptive changes in renal acidification in response to chronic respiratory acidosis

1985 ◽  
Vol 248 (4) ◽  
pp. F492-F499 ◽  
Author(s):  
R. L. Tannen ◽  
B. Hamid
Keyword(s):  
Metabolic Acidosis ◽  
Proton Transport ◽  
Respiratory Acidosis ◽  
Hydrogen Ion ◽  
Distal Nephron ◽  
Urine Ph ◽  
Chronic Metabolic Acidosis ◽  
Adaptive Changes ◽  
Secretory Capacity

To examine whether chronic respiratory acidosis results in adaptive changes in renal acidification, rats were housed for 3 days in an environmental chamber with an ambient CO2 content of 10% and their kidneys were perfused in vitro according to two protocols. To assess hydrogen ion secretory capacity of the distal nephron, perfusions were carried out with a low bicarbonate concentration, in the absence of ammoniagenic substrate, and with saturating quantities of the buffer creatinine. Under these conditions, the titration of creatinine at a pH less than 6.0 (TA pH 6.0) reflects the H+ secretory capacity of a discrete functional segment of the distal nephron. Kidneys from rats with chronic respiratory acidosis exhibited a significantly lower urine pH and higher rate of TA pH 6.0 than controls perfused in this fashion, indicative of an adaptive increase in the distal nephron capacity for proton transport. This adaptation was comparable with that reported previously for rats exposed to chronic metabolic acidosis. Furthermore, evidence of adaptation persisted in the presence of amiloride (10(-5) M), suggesting that it reflects, at least in part, a sodium-independent mechanism of proton transport. Hydrogen ion secretion by the proximal nephron was assessed by performing standard bicarbonate titration curves with kidneys from rats with chronic respiratory acidosis, chronic metabolic acidosis, and controls using a perfusate equilibrated with 95% O2/5% CO2.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans

2020 ◽  
Author(s):  
Verena Klämbt ◽  
Max Werth ◽  
Ana C Onuchic-Whitford ◽  
Maike Getwan ◽  
Thomas M Kitzler ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Kidney Development ◽  
Renal Tubules ◽  
Loss Of Function ◽  
Distal Nephron ◽  
Truncating Mutation ◽  
Whole Exome ◽  
Hypokalemic Alkalosis ◽  
Echogenic Kidneys

Abstract Background An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis. Methods In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD. Results We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity. Conclusion Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

Relation of membrane potential to basolateral TEA transport in isolated snake proximal renal tubules

1995 ◽  
Vol 268 (6) ◽  
pp. R1539-R1545 ◽  
Author(s):  
Y. K. Kim ◽  
W. H. Dantzler
Keyword(s):  
Steady State ◽  
Membrane Potential ◽  
Potent Inhibitor ◽  
Basolateral Membrane ◽  
Potential Difference ◽  
Renal Tubules ◽  
K Concentration ◽  
Electrochemical Equilibrium ◽  
Membrane Potential Difference ◽  
Basolateral Membrane Potential

We measured the effects of changes in bath K+ concentration ([K+]) on basolateral membrane potential difference (PD) and [3H]tetraethylammonium (TEA) transport in isolated snake (Thamnophis) proximal renal tubules (25 degrees C; pH 7.4). Increasing bath [K+] from 3 to 65 mM decreased PD from -60 mV (inside of cells negative) to -20 mV and 2-min uptake of [3H]TEA by approximately 25%, indicating that PD influences TEA entry into the cells. Uptake of [3H]TEA was inhibited similarly at both K+ concentrations by unlabeled TEA, indicating that uptake is carrier mediated. Kt (approximately 18 microM) for 2-min uptake of [3H]TEA in 3 mM K+ increased significantly in 65 mM K+, suggesting that the decrease in PD or the increase in [K+] alters the affinity of the transporter for TEA. The steady-state cell-to-bath ratio for [3H]TEA with 3 mM K+ (-60 mV PD) was approximately 16, significantly above the ratio of 10 predicted for passive distribution at electrochemical equilibrium. With 65 mM K+ (-20 mV PD) this ratio decreased to approximately 6, again significantly above the predicted ratio of 2. These data suggest that the PD can account for much, but not all, of the steady-state uptake of TEA. Efflux of [3H]TEA across the basolateral membrane was identical with either 3 or 65 mM K+ in the bath but was almost completely inhibited in either case by tetrapentylammonium, a potent inhibitor of TEA uptake. These data indicate that virtually all TEA transport across the basolateral membrane is carrier mediated and that transport out of the cells is unaffected by PD.

Intracellular potentials in rabbit proximal tubules perfused in vitro

1981 ◽  
Vol 240 (3) ◽  
pp. F200-F210 ◽  
Author(s):  
B. Biagi ◽  
T. Kubota ◽  
M. Sohtell ◽  
G. Giebisch
Keyword(s):  
Membrane Potential ◽  
Basolateral Membrane ◽  
Proximal Tubules ◽  
Rabbit Kidney ◽  
Electrical Measurements ◽  
Proximal Tubular ◽  
The Mean ◽  
Number Of Cells ◽  
Basolateral Membrane Potential

Conventional microelectrodes were used to measure the basolateral membrane potential (VBL) in isolated perfused superficial proximal convoluted (sPCT) and superficial proximal straight (sPST) tubules of the rabbit kidney. Stable recordings for periods up to 2 h can be obtained. The mean +/- SE (n = number of cells) values of VBL were sPCT = -51.0 +/- 1.63 (24) and sPST = -47.0 +/- 0.97 (94) mV. Inhibitors of active transport, ouabain (10(-5) M) and low bath potassium (0.1 mM), caused a significant depolarization of VBL in sPST. In contrast, short-duration bath cooling (10 degrees C) had no significant effect. Removal of luminal glucose caused a larger hyperpolarization in sPCT (-13.9 +/- 1.77 (9) mV) than in sPST (-3.8 +/- 1.02 (5) mV). Removal of luminal glucose and alanine resulted in an even larger hyperpolarization of VBL in sPCT (-19.0 +/- 0.44 (6) mV). Perfusion of the lumen with a solution resembling late proximal tubular fluid in sPST resulted in hyperpolarization of VBL (-4.3 +/- 0.85 (4) mV). Reducing bath pH to 6.7 depolarized VBL (39.9 +/- 1.77 (13) mV). This effect can be associated with a decrease in the relative potassium permeability of the basolateral membrane. These results demonstrate the feasibility of using intracellular electrical measurements to determine both luminal and basolateral membrane characteristics in isolated proximal tubular segments.

Glutamine transport in renal basolateral vesicles from dogs with metabolic acidosis

1984 ◽  
Vol 246 (1) ◽  
pp. F78-F86 ◽  
Author(s):  
D. W. Windus ◽  
D. E. Cohn ◽  
S. Klahr ◽  
M. R. Hammerman
Keyword(s):  
Metabolic Acidosis ◽  
Initial Rate ◽  
Basolateral Membrane ◽  
Cortical Cell ◽  
Membrane Vesicles ◽  
Ammonia Production ◽  
Basolateral Membrane Vesicles ◽  
Electrogenic Transport ◽  
Chronic Metabolic Acidosis ◽  
Glutamine Transport

To determine whether the increased ammonia production per nephron in chronic metabolic acidosis is accompanied by augmented L-glutamine transport across the basolateral membrane of the renal cortical cell and consequent increased availability of this ammoniagenic amino acid, we measured L-[3H]glutamine transport in basolateral membrane vesicles (BLMV) isolated from kidneys of normal and acidotic dogs. Na+ -dependent electrogenic transport of L-[3H]glutamine was demonstrated in BLMV from kidneys of normal dogs that exhibited saturability over the concentration range of 25 microM to 2 mM L-glutamine. The apparent Km was 416 +/- 114 microM and Vmax was 536 +/- 129 pmol X mg protein-1 X 15 s-1. The initial rate of Na+ -dependent L-[3H]glutamine transport was increased in BLMV from kidneys of acidotic dogs, as reflected by an increased apparent Vmax. We conclude that an adaptation resulting in greater uptake of L-glutamine across the basolateral membrane of the renal cortical cell may underlie, in part, the increased rate of ammonia production per nephron seen in chronic metabolic acidosis.

Direct measurement of basolateral membrane potentials from cells of the macula densa

1989 ◽  
Vol 257 (3) ◽  
pp. F463-F468 ◽  
Author(s):  
P. D. Bell ◽  
J. Y. Lapointe ◽  
J. Cardinal
Keyword(s):  
Membrane Potential ◽  
Direct Measurement ◽  
Basolateral Membrane ◽  
Membrane Potentials ◽  
Macula Densa ◽  
Rabbit Kidney ◽  
Fluid Composition ◽  
Nacl Solution ◽  
Basolateral Membrane Potential

At the present time, little is known concerning the electrophysiology of the cells of the macula densa and whether or not these cells are electrically responsive to alterations in luminal fluid composition. To investigate this issue, cortical thick ascending limbs (CTAL) containing macula densa and attached glomeruli were dissected from rabbit kidney and the CTAL perfused in vitro. Basolateral membrane potential (Vbl) was measured with microelectrodes in macula densa cells and, for comparison, in cells of the CTAL. Macula densa Vbl averaged -56.5 +/- 7.6 mV (n = 4) at a (n = 22) at 20 mM NaCl, -35.6 +/- 3.9 mV (n = 16) at 45 mM NaCl, and -25.5 +/- 2.6 mV (n = 32) at 150 mm NaCl. Thus macula densa Vbl depolarized markedly (31 mV) when luminal perfusate [NaCl] was increased from low to high values. In contrast, Vbl measured in CTAL cells averaged -62 +/- 6.1 mV (n = 6) in 45 mM NaCl and did not change significantly as perfusate NaCl was increased to 150 mM. In the presence of 150 mM NaCl, luminal application of furosemide (50 microM) produced a small (3.5 +/- 1.1 mV, n = 16) but statistically significant (P less than 0.02) hyperpolarization in macula densa cells, whereas CTAL cell Vbl hyperpolarized markedly (20 +/- 5.7 mV, n = 6) with addition of furosemide. Finally, neither macula densa cells nor the CTAL cells changed Vbl when 45 mM NaCl solution was made hypotonic by removing mannitol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hyperosmotic challenge on basolateral membrane potential in rabbit urinary bladder

1990 ◽  
Vol 258 (2) ◽  
pp. C248-C257 ◽  
Author(s):  
P. J. Donaldson ◽  
S. A. Lewis
Keyword(s):  
Membrane Potential ◽  
Urinary Bladder ◽  
Basolateral Membrane ◽  
Pump Current ◽  
Bathing Solution ◽  
Partial Recovery ◽  
Parallel Operation ◽  
Voltage Recovery ◽  
Rabbit Urinary Bladder ◽  
Basolateral Membrane Potential

In the rabbit urinary bladder, serosal hyperosmotic challenge (SHOC) with either 33 mM NaCl or 66 mM mannitol caused basolateral membrane potential (Vbl) to initially depolarize from -52.6 +/- 1.6 to -48.4 +/- 1.4 mV, followed by a recovery of Vbl to -57.5 +/- 1.3 mV after 13.7 +/- 1.0 min. The voltage recovery was dependent on both serosal HCO3- and Cl-, and in the absence of both, Vbl depolarized to -11.6 +/- 1.5 mV and the ratio of apical-to-basolateral resistance (Ra/Rbl) decreased from 21.0 +/- 3.4 to 8.3 +/- 3.1. This decrease in Ra/Rbl and consequent depolarization of Vbl is caused by a decrease in basolateral K+ conductance. Replacement of serosal Cl- with NO3- or SCN- followed by SHOC caused a sustained depolarization of Vbl to -32.5 +/- 4.4 and -40.9 +/- 0.9 mV, respectively. However, when Br- was used to replace Cl-, voltage recovery occurred but was slowed (24.0 +/- 2.7 min) and reduced in magnitude (-47.5 +/- 3.5 mV). Addition of amiloride (1 mM) or niflumic acid (100 microM), but not bumetanide (1 microM), to the serosal bathing solution inhibited voltage recovery causing Vbl to depolarize to -36.3 +/- 2.6 and -41.5 +/- 4.5 mV, respectively. Serosal addition of ouabain after SHOC caused Vbl to depolarize by 10.8 +/- 0.9 mV in 2 min. We speculate that the SHOC-induced initial depolarization of Vbl is a loss of Ba2(+)-sensitive K+ conductance caused by cell shrinkage. The subsequent repolarization/hyperpolarization of Vbl is caused by an enhanced basolateral membrane Na+ pump current and a reappearance of the Ba2(+)-sensitive K+ conductance. The parallel operation of Na(+)-H+ and Cl(-)-HCO3- exchanges will then supply Na+ for the pump current and, via cellular accumulation of Na+, K+, and Cl-, might result in a partial recovery of cell volume and thus Ba2(+)-sensitive K+ conductance.

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