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Article ; Online: Base (HCO3-/CO32-) Transport Properties of SLC4 Proteins: New Insights in Acid-Base Kidney Physiology.

Kurtz, Ira / Schwartz, George J

Journal of the American Society of Nephrology : JASN

2023 Volume 34, Issue 1, Page(s) 8–13

Abstract: H+ or base transporters and channels in the mammalian genome play important roles in the maintenance of numerous cellular biochemical and physiologic processes throughout the body. Among the known base transporters, those within the SLC4 and SLC26 gene ... ...

Abstract	H+ or base transporters and channels in the mammalian genome play important roles in the maintenance of numerous cellular biochemical and physiologic processes throughout the body. Among the known base transporters, those within the SLC4 and SLC26 gene families are involved in cell, transepithelial, and whole organ function. Whether the functional properties of these transporters involve HCO3-, CO32-, or HCO3-/CO32- stimulated H+ (or OH-) transport has not received widespread attention in the literature. Accordingly, "bicarbonate" is the term typically used in most textbooks without greater specificity. Moreover, clinicians and physiologists have historically focused on the blood HCO3- concentration as the base term in the Henderson-Hasselbalch equation in the analysis of clinical acid-base abnormalities, thus, bicarbonate has been assumed to be the species reabsorbed along the nephron as required to maintain the blood [HCO3-] at approximately 25 mM. However, accumulating data in the literature suggest that carbonate, rather than bicarbonate, is the species absorbed across the proximal tubule basolateral membrane, whereas in the collecting duct, bicarbonate is indeed transported. Various experimental approaches leading to this new concept are herein reviewed.
MeSH term(s)	Animals ; Bicarbonates/metabolism ; Membrane Transport Proteins ; Kidney Tubules, Proximal/metabolism ; Cell Membrane/metabolism ; Mammals/metabolism
Chemical Substances	Bicarbonates ; Membrane Transport Proteins
Language	English
Publishing date	2023-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000008
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Article ; Online: Renal Tubular Acidosis: H

Kurtz, Ira

Advances in chronic kidney disease

2018 Volume 25, Issue 4, Page(s) 334–350

Abstract: Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal ... ...

Abstract	Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal HCO
MeSH term(s)	Acid-Base Imbalance ; Acidosis, Renal Tubular/complications ; Acidosis, Renal Tubular/physiopathology ; Ammonia/metabolism ; Ammonium Compounds/urine ; Animals ; Bicarbonates/metabolism ; Biological Transport ; Calcium/metabolism ; Citric Acid/urine ; Humans ; Hypercalciuria/etiology ; Hypokalemia/etiology ; Ketoglutaric Acids/metabolism ; Kidney Tubules, Distal/physiopathology ; Kidney Tubules, Proximal/physiopathology ; Sodium-Bicarbonate Symporters/genetics
Chemical Substances	Ammonium Compounds ; Bicarbonates ; Ketoglutaric Acids ; SLC4A4 protein, human ; Sodium-Bicarbonate Symporters ; Citric Acid (2968PHW8QP) ; Ammonia (7664-41-7) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2018-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	1548-5609 ; 1548-5595
ISSN (online)	1548-5609
ISSN	1548-5595
DOI	10.1053/j.ackd.2018.05.005
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Article ; Online: Impact of various buffers and weak bases on lysosomal and intracellular pH: Implications for infectivity of SARS-CoV-2.

Kraut, Jeffrey A / Cheetham-Wilkinson, Izaak J / Swan, Laura E / Stagi, Massimiliano / Kurtz, Ira

FASEB bioAdvances

2023 Volume 5, Issue 4, Page(s) 149–155

Abstract: Acidification of the cellular lysosome is an important factor in infection of mammalian cells by SARS-CoV-2. Therefore, raising the pH of the lysosome would theoretically be beneficial in prevention or treatment of SARS-CoV-2 infection. Sodium ... ...

Abstract	Acidification of the cellular lysosome is an important factor in infection of mammalian cells by SARS-CoV-2. Therefore, raising the pH of the lysosome would theoretically be beneficial in prevention or treatment of SARS-CoV-2 infection. Sodium bicarbonate, carbicarb, and THAM are buffers that can be used clinically to provide base to patients. To examine whether these bases could raise lysosomal pH and therefore be a primary or adjunctive treatment of SARS-CoV-2 infection, we measured lysosomal and intracellular pH of mammalian cells after exposure to each of these bases. Mammalian HEK293 cells expressing RpH-LAMP1-3xFLAG, a ratiometric sensor of lysosomal luminal pH, were first exposed to Hepes which was then switched to sodium bicarbonate, carbicarb, or THAM and lysosomal pH measured. In bicarbonate buffer the mean lysosomal pH was 4.3 ± 0.1 (
Language	English
Publishing date	2023-03-15
Publishing country	United States
Document type	Journal Article
ISSN	2573-9832
ISSN (online)	2573-9832
DOI	10.1096/fba.2022-00062
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Article ; Online: Molecular mechanisms and regulation of urinary acidification.

Kurtz, Ira

Comprehensive Physiology

2014 Volume 4, Issue 4, Page(s) 1737–1774

Abstract: The H(+) concentration in human blood is kept within very narrow limits, ~40 nmol/L, despite the fact that dietary metabolism generates acid and base loads that are added to the systemic circulation throughout the life of mammals. One of the primary ... ...

Abstract	The H(+) concentration in human blood is kept within very narrow limits, ~40 nmol/L, despite the fact that dietary metabolism generates acid and base loads that are added to the systemic circulation throughout the life of mammals. One of the primary functions of the kidney is to maintain the constancy of systemic acid-base chemistry. The kidney has evolved the capacity to regulate blood acidity by performing three key functions: (i) reabsorb HCO3(-) that is filtered through the glomeruli to prevent its excretion in the urine; (ii) generate a sufficient quantity of new HCO3(-) to compensate for the loss of HCO3(-) resulting from dietary metabolic H(+) loads and loss of HCO3(-) in the urea cycle; and (iii) excrete HCO3(-) (or metabolizable organic anions) following a systemic base load. The ability of the kidney to perform these functions requires that various cell types throughout the nephron respond to changes in acid-base chemistry by modulating specific ion transport and/or metabolic processes in a coordinated fashion such that the urine and renal vein chemistry is altered appropriately. The purpose of the article is to provide the interested reader with a broad review of a field that began historically ~60 years ago with whole animal studies, and has evolved to where we are currently addressing questions related to kidney acid-base regulation at the single protein structure/function level.
MeSH term(s)	Acidosis, Renal Tubular/genetics ; Acidosis, Renal Tubular/metabolism ; Animals ; Humans ; Kidney Tubules/metabolism ; Potassium Channels/genetics ; Potassium Channels/metabolism ; Sodium-Bicarbonate Symporters/genetics ; Sodium-Bicarbonate Symporters/metabolism ; Sodium-Hydrogen Exchangers/genetics ; Sodium-Hydrogen Exchangers/metabolism ; Water-Electrolyte Balance
Chemical Substances	Potassium Channels ; Sodium-Bicarbonate Symporters ; Sodium-Hydrogen Exchangers
Language	English
Publishing date	2014-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2040-4603
ISSN (online)	2040-4603
DOI	10.1002/cphy.c140021
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Article ; Online: NBCe1 as a model carrier for understanding the structure-function properties of Na⁺ -coupled SLC4 transporters in health and disease.

Kurtz, Ira

Pflugers Archiv : European journal of physiology

2014 Volume 466, Issue 8, Page(s) 1501–1516

Abstract: SLC4 transporters are membrane proteins that in general mediate the coupled transport of bicarbonate (carbonate) and share amino acid sequence homology. These proteins differ as to whether they also transport Na(+) and/or Cl(-), in addition to their ... ...

Abstract	SLC4 transporters are membrane proteins that in general mediate the coupled transport of bicarbonate (carbonate) and share amino acid sequence homology. These proteins differ as to whether they also transport Na(+) and/or Cl(-), in addition to their charge transport stoichiometry, membrane targeting, substrate affinities, developmental expression, regulatory motifs, and protein-protein interactions. These differences account in part for the fact that functionally, SLC4 transporters have various physiological roles in mammals including transepithelial bicarbonate transport, intracellular pH regulation, transport of Na(+) and/or Cl(-), and possibly water. Bicarbonate transport is not unique to the SLC4 family since the structurally unrelated SLC26 family has at least three proteins that mediate anion exchange. The present review focuses on the first of the sodium-dependent SLC4 transporters that was identified whose structure has been most extensively studied: the electrogenic Na(+)-base cotransporter NBCe1. Mutations in NBCe1 cause proximal renal tubular acidosis (pRTA) with neurologic and ophthalmologic extrarenal manifestations. Recent studies have characterized the important structure-function properties of the transporter and how they are perturbed as a result of mutations that cause pRTA. It has become increasingly apparent that the structure of NBCe1 differs in several key features from the SLC4 Cl(-)-HCO3 (-) exchanger AE1 whose structural properties have been well-studied. In this review, the structure-function properties and regulation of NBCe1 will be highlighted, and its role in health and disease will be reviewed in detail.
MeSH term(s)	Acidosis, Renal Tubular/genetics ; Acidosis, Renal Tubular/physiopathology ; Animals ; Biological Transport/genetics ; Chloride-Bicarbonate Antiporters/physiology ; Humans ; Membrane Transport Proteins/physiology ; SLC4A Proteins/physiology ; Sodium-Bicarbonate Symporters/physiology ; Structure-Activity Relationship
Chemical Substances	Chloride-Bicarbonate Antiporters ; Membrane Transport Proteins ; SLC4A Proteins ; Sodium-Bicarbonate Symporters
Language	English
Publishing date	2014-02-11
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-014-1448-8
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Article ; Online: Impact of various buffers and weak bases on lysosomal and intracellular pH

Jeffrey A. Kraut / Izaak J. Cheetham‐Wilkinson / Laura E. Swan / Massimiliano Stagi / Ira Kurtz

FASEB BioAdvances, Vol 5, Iss 4, Pp 149-

Implications for infectivity of SARS‐CoV‐2

2023 Volume 155

Abstract: Abstract Acidification of the cellular lysosome is an important factor in infection of mammalian cells by SARS‐CoV‐2. Therefore, raising the pH of the lysosome would theoretically be beneficial in prevention or treatment of SARS‐CoV‐2 infection. Sodium ... ...

Abstract	Abstract Acidification of the cellular lysosome is an important factor in infection of mammalian cells by SARS‐CoV‐2. Therefore, raising the pH of the lysosome would theoretically be beneficial in prevention or treatment of SARS‐CoV‐2 infection. Sodium bicarbonate, carbicarb, and THAM are buffers that can be used clinically to provide base to patients. To examine whether these bases could raise lysosomal pH and therefore be a primary or adjunctive treatment of SARS‐CoV‐2 infection, we measured lysosomal and intracellular pH of mammalian cells after exposure to each of these bases. Mammalian HEK293 cells expressing RpH‐LAMP1‐3xFLAG, a ratiometric sensor of lysosomal luminal pH, were first exposed to Hepes which was then switched to sodium bicarbonate, carbicarb, or THAM and lysosomal pH measured. In bicarbonate buffer the mean lysosomal pH was 4.3 ± 0.1 (n = 20); p = NS versus Hepes (n = 20). The mean lysosomal pH in bicarbonate/carbonate was 4.3 ± 0.1 (n = 21) versus Hepes (n = 21), p = NS. In THAM buffer the mean lysosomal pH was 4.7 ± 0.07 (n = 20) versus Hepes (4.6 ± 0.1, n = 20), p = NS. In addition, there was no statistical difference between pHi in bicarbonate, carbicarb or THAM solutions. Using the membrane permeable base NH4Cl (5 mM), lysosomal pH increased significantly to 5.9 ± 0.1 (n = 21) compared to Hepes (4.5 ± 0.07, n = 21); p < 0.0001. Similarly, exposure to 1 mM hydroxychloroquine significantly increased the lysosomal pH to (5.9 ± 0.06, n = 20) versus Hepes (4.3 ± 0.1, n = 20), p < 0.0001. Separately steady‐state pHi was measured in HEK293 cells bathed in various buffers. In bicarbonate pHi was 7.29 ± 0.02 (n = 12) versus Hepes (7.45 ± 0.03, [n = 12]), p < 0.001. In cells bathed in carbicarb pHi was 7.27 ± 0.02 (n = 5) versus Hepes (7.43 ± 0.04, [n = 5]), p < 0.01. Cells bathed in THAM had a pHi of 7.25 ± 0.03 (n = 12) versus Hepes (7.44 ± 0.03 [n = 12]), p < 0.001. In addition, there was no statistical difference in pHi in bicarbonate, carbicarb or THAM solutions. The results of ...
Keywords	alkalinization ; carbicarb ; lysosomal pH ; sars‐Covid‐ 19 ; sodium bicarbonate ; tham ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article: Calcium Transport in the Kidney and Disease Processes.

Hanna, Ramy M / Ahdoot, Rebecca S / Kalantar-Zadeh, Kamyar / Ghobry, Lena / Kurtz, Ira

Frontiers in endocrinology

2022 Volume 12, Page(s) 762130

Abstract: Calcium is a key ion involved in cardiac and skeletal muscle contractility, nerve function, and skeletal structure. Global calcium balance is affected by parathyroid hormone and vitamin D, and calcium is shuttled between the extracellular space and the ... ...

Abstract	Calcium is a key ion involved in cardiac and skeletal muscle contractility, nerve function, and skeletal structure. Global calcium balance is affected by parathyroid hormone and vitamin D, and calcium is shuttled between the extracellular space and the bone matrix compartment dynamically. The kidney plays an important role in whole-body calcium balance. Abnormalities in the kidney transport proteins alter the renal excretion of calcium. Various hormonal and regulatory pathways have evolved that regulate the renal handling of calcium to maintain the serum calcium within defined limits despite dynamic changes in dietary calcium intake. Dysregulation of renal calcium transport can occur pharmacologically, hormonally, and
MeSH term(s)	Calcium/metabolism ; Kidney/metabolism ; Parathyroid Hormone/metabolism ; Phosphates ; Vitamin D/physiology
Chemical Substances	Parathyroid Hormone ; Phosphates ; Vitamin D (1406-16-2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-03-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2021.762130
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Article: Coarse-grained molecular dynamics simulations of lipid-protein interactions in SLC4 proteins.

Zhekova, Hristina R / Ramirez-Echemendía, Daniel P / Sejdiu, Besian I / Pushkin, Alexander / Tieleman, D Peter / Kurtz, Ira

bioRxiv : the preprint server for biology

2023

Abstract: The SLC4 family of secondary bicarbonate transporters is responsible for the transport of HCO : Statement of significance: The SLC4 protein family is involved in critical physiological processes like pH and blood pressure regulation and maintenance of ...

Abstract	The SLC4 family of secondary bicarbonate transporters is responsible for the transport of HCO Statement of significance: The SLC4 protein family is involved in critical physiological processes like pH and blood pressure regulation and maintenance of ion homeostasis. Its members can be found in various tissues. A number of studies suggest possible lipid regulation of the SLC4 function. However, the protein-lipid interactions in the SLC4 family are still poorly understood. Here we make use of long coarse-grained molecular dynamics simulations to assess the protein-lipid interactions in three SLC4 proteins with different transport modes, AE1, NBCe1, and NDCBE. We identify putative lipid binding sites for several lipid types of potential mechanistic importance, discuss them in the framework of the known experimental data and provide a necessary basis for further studies on lipid regulation of SLC4 function.
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.26.546592
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Article ; Online: The apical Na

Yang, Ning-Yan / Mukaibo, Taro / Kurtz, Ira / Melvin, James E

Journal of cellular physiology

2019 Volume 234, Issue 9, Page(s) 16376–16388

Abstract: ... The ... ...

Abstract	The HCO
Language	English
Publishing date	2019-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.28306
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Article: Data-driven prediction of continuous renal replacement therapy survival.

Zamanzadeh, Davina / Feng, Jeffrey / Petousis, Panayiotis / Vepa, Arvind / Sarrafzadeh, Majid / Karumanchi, S Ananth / Bui, Alex A T / Kurtz, Ira

Research square

2023

Abstract: Continuous renal replacement therapy (CRRT) is a form of dialysis prescribed to severely ill patients who cannot tolerate regular hemodialysis. However, as the patients are typically very ill to begin with, there is always uncertainty as to whether they ... ...

Abstract	Continuous renal replacement therapy (CRRT) is a form of dialysis prescribed to severely ill patients who cannot tolerate regular hemodialysis. However, as the patients are typically very ill to begin with, there is always uncertainty as to whether they will survive during or after CRRT treatment. Because of outcome uncertainty, a large percentage of patients treated with CRRT do not survive, utilizing scarce resources and raising false hope in patients and their families. To address these issues, we present a machine-learning-based algorithm to predict if patients will survive after being treated with CRRT. We use information extracted from electronic health records from patients who were placed on CRRT at multiple institutions to train a model that predicts CRRT survival outcome; on a held-out test set, the model achieved an area under the receiver operating curve of 0.929 (CI=0.917-0.942). Feature importance, error, and subgroup analyses identified consistently, mean corpuscular volume as a driving feature for model predictions. Overall, we demonstrate the potential for predictive machine-learning models to assist clinicians in alleviating the uncertainty of CRRT patient survival outcomes, with opportunities for future improvement through further data collection and advanced modeling.
Language	English
Publishing date	2023-11-14
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3487939/v1
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