The Experts below are selected from a list of 159852483 Experts worldwide ranked by ideXlab platform
Heini Murer - One of the best experts on this subject based on the ideXlab platform.
-
Mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:In the past 25 years, the cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the Na^+-dependent inorganic phosphate (P_i) cotransporters NaPi-IIa, NaPi-IIb and NaPi-IIc, respectively, has enabled study of the molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. Dietary factors, particularly dietary P_i, as well as hormones and phosphatonins, including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), regulate the expression and activity of the P_i transporters through transcriptional, translational and post-translational mechanisms that involve interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking via endocytosis or exocytosis. Mutations in any of the three transporters can cause dysregulation of epithelial P_i transport, can affect serum P_i levels and can cause damage of various target organs in both humans and rodents, highlighting the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional studies together with structure–function studies have provided insights into the transport mechanisms of the NaPi-II cotransporter. The development of small molecules that modify the activity of P_i transporters holds promise for the maintenance of P_i homeostasis in patients with chronic kidney disease and other disorders associated with hyperphosphataemia and its severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms. Over the past 25 years, successive cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the sodium-dependent inorganic phosphate (P_i) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. P_i and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P_i transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P_i transport with effects on serum P_i levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P_i, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P_i homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms.
-
Mechanisms of phosphate transport.
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
renal specific and inducible depletion of napi iic SLC34A3 the cotransporter mutated in hhrh does not affect phosphate or calcium homeostasis in mice
American Journal of Physiology-renal Physiology, 2014Co-Authors: Komuraiah Myakala, Sarah E. Motta, Carsten A Wagner, Jürg Biber, Heini Murer, Robert Koesters, Nati HernandoAbstract:The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of Pi whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary Pi, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney.
-
Renal-specific and inducible depletion of NaPi-IIc/SLC34A3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice.
American journal of physiology. Renal physiology, 2014Co-Authors: Komuraiah Myakala, Sarah E. Motta, Carsten A Wagner, Jürg Biber, Heini Murer, Robert Koesters, Nati HernandoAbstract:The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of Pi whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary Pi, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney.
Jürg Biber - One of the best experts on this subject based on the ideXlab platform.
-
renal specific and inducible depletion of napi iic SLC34A3 the cotransporter mutated in hhrh does not affect phosphate or calcium homeostasis in mice
American Journal of Physiology-renal Physiology, 2014Co-Authors: Komuraiah Myakala, Sarah E. Motta, Carsten A Wagner, Jürg Biber, Heini Murer, Robert Koesters, Nati HernandoAbstract:The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of Pi whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary Pi, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney.
-
Renal-specific and inducible depletion of NaPi-IIc/SLC34A3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice.
American journal of physiology. Renal physiology, 2014Co-Authors: Komuraiah Myakala, Sarah E. Motta, Carsten A Wagner, Jürg Biber, Heini Murer, Robert Koesters, Nati HernandoAbstract:The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of Pi whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary Pi, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney.
-
Genetic diseases of renal phosphate handling.
Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2014Co-Authors: Carsten A Wagner, Isabel Rubio-aliaga, Jürg Biber, Nati HernandoAbstract:Renal control of systemic phosphate homeostasis is critical as evident from inborn and acquired diseases causing renal phosphate wasting. At least three transport proteins are responsible for renal phosphate reabsorption: NAPI-IIa (SLC34A1), NAPI-IIc (SLC34A3) and PIT-2 (SLC20A2). These transporters are highly regulated by various cellular mechanisms and factors including acid-base status, electrolyte balance and hormones such as dopamine, glucocorticoids, growth factors, vitamin D3, parathyroid hormone and fibroblast growth factor 23 (FGF23). Whether renal phosphate wasting is caused by inactivating mutations in the NAPI-IIa transporter is controversial. Mutations in the NAPI-IIc transporter cause hereditary hypophosphatemic rickets with hypercalciuria. Besides the primary inherited defects, there are also inherited defects in major regulators of phosphate homeostasis that lead to alterations in phosphate handling. Autosomal dominant hypophosphatemic rickets is due to FGF23 mutations leading to resistance against its own degradation. Similarly, inactivating mutations in the PHEX gene, which causes FGF23 inactivation, cause X-linked hypophosphatemia due to renal phosphate losses. In contrast, mutations in galactosamine:polypeptide N-acetyl-galactosaminyltransferase, responsible for O-glycosylation of FGF23, or in klotho, a cofactor for FGF23 signalling result in hyperphosphatemia. Acquired syndromes of renal phosphate wasting, hypophosphatemia and osteomalacia (tumour-associated osteomalacia) can be due to the excessive synthesis or release of phosphaturic factors (FGF23, FGF-7, MEPE and sFRP4) from mesenchymal tumours. bone, FGF23, kidney, phosphate, PTH. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
-
The SLC34 family of sodium-dependent phosphate transporters
Pflügers Archiv: European Journal of Physiology, 2013Co-Authors: Carsten A Wagner, Nati Hernando, Ian C. Forster, Jürg BiberAbstract:The SLC34 family of sodium-driven phosphate cotransporters comprises three members: NaPi-IIa (SLC34A1), NaPi-IIb (SLC34A2), and NaPi-IIc (SLC34A3). These transporters mediate the translocation of divalent inorganic phosphate (HPO4 2−) together with two (NaPi-IIc) or three sodium ions (NaPi-IIa and NaPi-IIb), respectively. Consequently, phosphate transport by NaPi-IIa and NaPi-IIb is electrogenic. NaPi-IIa and NaPi-IIc are predominantly expressed in the brush border membrane of the proximal tubule, whereas NaPi-IIb is found in many more organs including the small intestine, lung, liver, and testis. The abundance and activity of these transporters are mostly regulated by changes in their expression at the cell surface and are determined by interactions with proteins involved in scaffolding, trafficking, or intracellular signaling. All three transporters are highly regulated by factors including dietary phosphate status, hormones like parathyroid hormone, 1,25-OH2 vitamin D3 or FGF23, electrolyte, and acid–base status. The physiological relevance of the three members of the SLC34 family is underlined by rare Mendelian disorders causing phosphaturia, hypophosphatemia, or ectopic organ calcifications.
-
Phosphate transporters of the SLC20 and SLC34 families.
Molecular Aspects of Medicine, 2013Co-Authors: Ian C. Forster, Nati Hernando, Jürg Biber, Heini MurerAbstract:Transport of inorganic phosphate (Pi) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na(+)-dependent, secondary-active cotransporters to transport Pi across cell membranes. The SLC34 proteins are expressed in specific organs important for Pi homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in Pi reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates Pi absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity, regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarizes our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiology and pharmacology.
Carsten A Wagner - One of the best experts on this subject based on the ideXlab platform.
-
Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease
Pflügers Archiv - European Journal of Physiology, 2020Co-Authors: Sarah E. Motta, Pedro Henrique Imenez Silva, Betül Haykir, Eva Maria Pastor-arroyo, Carla Bettoni, Arezoo Daryadel, Nati Hernando, Carsten A WagnerAbstract:Na^+-coupled phosphate cotransporters from the SLC34 and SLC20 families of solute carriers mediate transepithelial transport of inorganic phosphate (Pi). NaPi-IIa/Slc34a1, NaPi-IIc/SLC34A3, and Pit-2/Slc20a2 are all expressed at the apical membrane of renal proximal tubules and therefore contribute to renal Pi reabsorption. Unlike NaPi-IIa and NaPi-IIc, which are rather kidney-specific, NaPi-IIb/Slc34a2 is expressed in several epithelial tissues, including the intestine, lung, testis, and mammary glands. Recently, the expression of NaPi-IIb was also reported in kidneys from rats fed on high Pi. Here, we systematically quantified the mRNA expression of SLC34 and SLC20 cotransporters in kidneys from mice, rats, and humans. In all three species, NaPi-IIa mRNA was by far the most abundant renal transcript. Low and comparable mRNA levels of the other four transporters, including NaPi-IIb, were detected in kidneys from rodents and humans. In mice, the renal expression of NaPi-IIa transcripts was restricted to the cortex, whereas NaPi-IIb mRNA was observed in medullary segments. Consistently, NaPi-IIb protein colocalized with uromodulin at the luminal membrane of thick ascending limbs of the loop of Henle segments. The abundance of NaPi-IIb transcripts in kidneys from mice was neither affected by dietary Pi, the absence of renal NaPi-IIc, nor the depletion of intestinal NaPi-IIb. In contrast, it was highly upregulated in a model of oxalate-induced kidney disease where all other SLC34 phosphate transporters were downregulated. Thus, NaPi-IIb may contribute to renal phosphate reabsorption, and its upregulation in kidney disease might promote hyperphosphatemia.
-
Mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:In the past 25 years, the cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the Na^+-dependent inorganic phosphate (P_i) cotransporters NaPi-IIa, NaPi-IIb and NaPi-IIc, respectively, has enabled study of the molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. Dietary factors, particularly dietary P_i, as well as hormones and phosphatonins, including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), regulate the expression and activity of the P_i transporters through transcriptional, translational and post-translational mechanisms that involve interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking via endocytosis or exocytosis. Mutations in any of the three transporters can cause dysregulation of epithelial P_i transport, can affect serum P_i levels and can cause damage of various target organs in both humans and rodents, highlighting the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional studies together with structure–function studies have provided insights into the transport mechanisms of the NaPi-II cotransporter. The development of small molecules that modify the activity of P_i transporters holds promise for the maintenance of P_i homeostasis in patients with chronic kidney disease and other disorders associated with hyperphosphataemia and its severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms. Over the past 25 years, successive cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the sodium-dependent inorganic phosphate (P_i) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. P_i and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P_i transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P_i transport with effects on serum P_i levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P_i, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P_i homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms.
-
Mechanisms of phosphate transport.
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
Renal phosphate handling and inherited disorders of phosphate reabsorption: an update
Pediatric Nephrology, 2019Co-Authors: Carsten A Wagner, Isabel Rubio-aliaga, Nati HernandoAbstract:Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na^+-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH)_2 vitamin D_3 as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi-IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date.
Nati Hernando - One of the best experts on this subject based on the ideXlab platform.
-
Expression of NaPi-IIb in rodent and human kidney and upregulation in a model of chronic kidney disease
Pflügers Archiv - European Journal of Physiology, 2020Co-Authors: Sarah E. Motta, Pedro Henrique Imenez Silva, Betül Haykir, Eva Maria Pastor-arroyo, Carla Bettoni, Arezoo Daryadel, Nati Hernando, Carsten A WagnerAbstract:Na^+-coupled phosphate cotransporters from the SLC34 and SLC20 families of solute carriers mediate transepithelial transport of inorganic phosphate (Pi). NaPi-IIa/Slc34a1, NaPi-IIc/SLC34A3, and Pit-2/Slc20a2 are all expressed at the apical membrane of renal proximal tubules and therefore contribute to renal Pi reabsorption. Unlike NaPi-IIa and NaPi-IIc, which are rather kidney-specific, NaPi-IIb/Slc34a2 is expressed in several epithelial tissues, including the intestine, lung, testis, and mammary glands. Recently, the expression of NaPi-IIb was also reported in kidneys from rats fed on high Pi. Here, we systematically quantified the mRNA expression of SLC34 and SLC20 cotransporters in kidneys from mice, rats, and humans. In all three species, NaPi-IIa mRNA was by far the most abundant renal transcript. Low and comparable mRNA levels of the other four transporters, including NaPi-IIb, were detected in kidneys from rodents and humans. In mice, the renal expression of NaPi-IIa transcripts was restricted to the cortex, whereas NaPi-IIb mRNA was observed in medullary segments. Consistently, NaPi-IIb protein colocalized with uromodulin at the luminal membrane of thick ascending limbs of the loop of Henle segments. The abundance of NaPi-IIb transcripts in kidneys from mice was neither affected by dietary Pi, the absence of renal NaPi-IIc, nor the depletion of intestinal NaPi-IIb. In contrast, it was highly upregulated in a model of oxalate-induced kidney disease where all other SLC34 phosphate transporters were downregulated. Thus, NaPi-IIb may contribute to renal phosphate reabsorption, and its upregulation in kidney disease might promote hyperphosphatemia.
-
Mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:In the past 25 years, the cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the Na^+-dependent inorganic phosphate (P_i) cotransporters NaPi-IIa, NaPi-IIb and NaPi-IIc, respectively, has enabled study of the molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. Dietary factors, particularly dietary P_i, as well as hormones and phosphatonins, including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), regulate the expression and activity of the P_i transporters through transcriptional, translational and post-translational mechanisms that involve interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking via endocytosis or exocytosis. Mutations in any of the three transporters can cause dysregulation of epithelial P_i transport, can affect serum P_i levels and can cause damage of various target organs in both humans and rodents, highlighting the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional studies together with structure–function studies have provided insights into the transport mechanisms of the NaPi-II cotransporter. The development of small molecules that modify the activity of P_i transporters holds promise for the maintenance of P_i homeostasis in patients with chronic kidney disease and other disorders associated with hyperphosphataemia and its severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms. Over the past 25 years, successive cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the sodium-dependent inorganic phosphate (P_i) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. P_i and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P_i transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P_i transport with effects on serum P_i levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P_i, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P_i homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms.
-
Mechanisms of phosphate transport.
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
Renal phosphate handling and inherited disorders of phosphate reabsorption: an update
Pediatric Nephrology, 2019Co-Authors: Carsten A Wagner, Isabel Rubio-aliaga, Nati HernandoAbstract:Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na^+-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH)_2 vitamin D_3 as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi-IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date.
Ian C. Forster - One of the best experts on this subject based on the ideXlab platform.
-
Mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:In the past 25 years, the cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the Na^+-dependent inorganic phosphate (P_i) cotransporters NaPi-IIa, NaPi-IIb and NaPi-IIc, respectively, has enabled study of the molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. Dietary factors, particularly dietary P_i, as well as hormones and phosphatonins, including parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), regulate the expression and activity of the P_i transporters through transcriptional, translational and post-translational mechanisms that involve interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking via endocytosis or exocytosis. Mutations in any of the three transporters can cause dysregulation of epithelial P_i transport, can affect serum P_i levels and can cause damage of various target organs in both humans and rodents, highlighting the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional studies together with structure–function studies have provided insights into the transport mechanisms of the NaPi-II cotransporter. The development of small molecules that modify the activity of P_i transporters holds promise for the maintenance of P_i homeostasis in patients with chronic kidney disease and other disorders associated with hyperphosphataemia and its severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms. Over the past 25 years, successive cloning of SLC34A1 , SLC34A2 and SLC34A3 , which encode the sodium-dependent inorganic phosphate (P_i) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P_i transport. P_i and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P_i transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P_i transport with effects on serum P_i levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P_i homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P_i, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P_i homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences. This Review describes the mechanisms by which dietary, hormonal and metabolic factors regulate the expression and function of sodium-dependent phosphate cotransporters. The authors discuss the consequences of dysregulated phosphate transport and how understanding of the structure–function relationships of the transporters provides insights into their transport mechanisms.
-
Mechanisms of phosphate transport.
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Victor Sorribas, Enrico Gratton, Carsten A Wagner, Nati Hernando, Ian C. Forster, Juerg Biber, Heini MurerAbstract:Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (Pi) cotransport proteins 2a–2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal Pi transport. Pi and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these Pi transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial Pi transport with effects on serum Pi levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic Pi homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport Pi, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain Pi homeostasis in patients with chronic kidney disease — a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
-
The SLC34 family of sodium-dependent phosphate transporters
Pflügers Archiv: European Journal of Physiology, 2013Co-Authors: Carsten A Wagner, Nati Hernando, Ian C. Forster, Jürg BiberAbstract:The SLC34 family of sodium-driven phosphate cotransporters comprises three members: NaPi-IIa (SLC34A1), NaPi-IIb (SLC34A2), and NaPi-IIc (SLC34A3). These transporters mediate the translocation of divalent inorganic phosphate (HPO4 2−) together with two (NaPi-IIc) or three sodium ions (NaPi-IIa and NaPi-IIb), respectively. Consequently, phosphate transport by NaPi-IIa and NaPi-IIb is electrogenic. NaPi-IIa and NaPi-IIc are predominantly expressed in the brush border membrane of the proximal tubule, whereas NaPi-IIb is found in many more organs including the small intestine, lung, liver, and testis. The abundance and activity of these transporters are mostly regulated by changes in their expression at the cell surface and are determined by interactions with proteins involved in scaffolding, trafficking, or intracellular signaling. All three transporters are highly regulated by factors including dietary phosphate status, hormones like parathyroid hormone, 1,25-OH2 vitamin D3 or FGF23, electrolyte, and acid–base status. The physiological relevance of the three members of the SLC34 family is underlined by rare Mendelian disorders causing phosphaturia, hypophosphatemia, or ectopic organ calcifications.
-
Phosphate transporters of the SLC20 and SLC34 families.
Molecular Aspects of Medicine, 2013Co-Authors: Ian C. Forster, Nati Hernando, Jürg Biber, Heini MurerAbstract:Transport of inorganic phosphate (Pi) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na(+)-dependent, secondary-active cotransporters to transport Pi across cell membranes. The SLC34 proteins are expressed in specific organs important for Pi homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in Pi reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates Pi absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity, regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarizes our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiology and pharmacology.
