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Carsten A. Wagner - One of the best experts on this subject based on the ideXlab platform.
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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, Nati Hernando, Pedro Henrique Imenez Silva, Arezoo Daryadel, Betül Haykir, Eva Maria Pastor-arroyo, Carla Bettoni, 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.
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Mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Ian C. Forster, Nati Hernando, Carsten A. Wagner, Enrico Gratton, Juerg Biber, Victor Sorribas, 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.
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Mechanisms of phosphate transport.
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Ian C. Forster, Nati Hernando, Carsten A. Wagner, Enrico Gratton, Juerg Biber, Victor Sorribas, 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.
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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.
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Clinical aspects of the phosphate transporters NaPi-IIa and NaPi-IIb: mutations and disease associations
Pflügers Archiv: European Journal of Physiology, 2018Co-Authors: Eleanor D. Lederer, Carsten A. WagnerAbstract:The Na-dependent phosphate transporter NaPi-IIa (SLC34A1) is mostly expressed in kidney, whereas NaPi-IIb (SLC34A2) has a wider tissue distribution with prominent expression in the lung and small intestine. NaPi-IIa is involved in renal reabsorption of inorganic phosphate (Pi) from urine, and patients with biallelic inactivating mutations in SLC34A1 develop hypophosphatemia, hypercalcemia, hypercalciuria and nephrocalcinosis, and nephrolithiasis in early childhood. Monoallelic mutations are frequent in the general population and may impact on the risk to develop kidney stones in adulthood. SNPs in close vicinity to the SLC34A1 locus associate with the risk to develop CKD. NaPi-IIb mediates high-affinity transport of Pi from the diet and appears to be mostly important during low Pi availability. Biallelic inactivating SLC34A2 mutations are found in patients with pulmonary alveolar microlithiasis, a lung disease characterized by the deposition of microcrystals. In contrast, no evidence for disturbed systemic Pi homeostasis has been reported in these patients to date. Nevertheless, NaPi-IIb-mediated intestinal Pi absorption may be a target for pharmaceutical interventions in patients with chronic kidney disease and Pi overload.
Nati Hernando - One of the best experts on this subject based on the ideXlab platform.
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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, Nati Hernando, Pedro Henrique Imenez Silva, Arezoo Daryadel, Betül Haykir, Eva Maria Pastor-arroyo, Carla Bettoni, 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.
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Mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Ian C. Forster, Nati Hernando, Carsten A. Wagner, Enrico Gratton, Juerg Biber, Victor Sorribas, 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.
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Mechanisms of phosphate transport.
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Ian C. Forster, Nati Hernando, Carsten A. Wagner, Enrico Gratton, Juerg Biber, Victor Sorribas, 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.
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intestinal depletion of napi iib SLC34A2 in mice renal and hormonal adaptation
Journal of Bone and Mineral Research, 2015Co-Authors: Nati Hernando, Heini Murer, Carsten A. Wagner, Komuraiah Myakala, Fabia Simona, Thomas Knopfel, Linto Thomas, Jürg BiberAbstract:The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications. Here we report the generation of a constitutive but intestinal-specific NaPi-IIb/SLC34A2-deficient mouse model. Constitutive intestinal ablation of NaPi-IIb results in viable pups with normal growth. Homozygous mice are characterized by fecal wasting of Pi and complete absence of Na/Pi cotransport activity in BBM vesicles (BBMVs) isolated from ileum. In contrast, the urinary excretion of Pi is reduced in these animals. The plasma levels of Pi are similar in wild-type and NaPi-IIb-deficient mice. In females, the reduced phosphaturia associates with higher expression of NaPi-IIa and higher Na/Pi cotransport activity in renal BBMVs, as well as with reduced plasma levels of intact FGF-23. A similar trend is found in males. Thus, NaPi-IIb is the only luminal Na(+) -dependent Pi transporter in the murine ileum and its absence is fully compensated for in adult females by a mechanism involving the bone-kidney axis. The contribution of this mechanism to the adaptive response is less apparent in adult males. © 2015 American Society for Bone and Mineral Research.
Heini Murer - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of phosphate transport
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Ian C. Forster, Nati Hernando, Carsten A. Wagner, Enrico Gratton, Juerg Biber, Victor Sorribas, 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.
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Mechanisms of phosphate transport.
Nature Reviews Nephrology, 2019Co-Authors: Moshe Levi, Ian C. Forster, Nati Hernando, Carsten A. Wagner, Enrico Gratton, Juerg Biber, Victor Sorribas, 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.
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intestinal depletion of napi iib SLC34A2 in mice renal and hormonal adaptation
Journal of Bone and Mineral Research, 2015Co-Authors: Nati Hernando, Heini Murer, Carsten A. Wagner, Komuraiah Myakala, Fabia Simona, Thomas Knopfel, Linto Thomas, Jürg BiberAbstract:The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications. Here we report the generation of a constitutive but intestinal-specific NaPi-IIb/SLC34A2-deficient mouse model. Constitutive intestinal ablation of NaPi-IIb results in viable pups with normal growth. Homozygous mice are characterized by fecal wasting of Pi and complete absence of Na/Pi cotransport activity in BBM vesicles (BBMVs) isolated from ileum. In contrast, the urinary excretion of Pi is reduced in these animals. The plasma levels of Pi are similar in wild-type and NaPi-IIb-deficient mice. In females, the reduced phosphaturia associates with higher expression of NaPi-IIa and higher Na/Pi cotransport activity in renal BBMVs, as well as with reduced plasma levels of intact FGF-23. A similar trend is found in males. Thus, NaPi-IIb is the only luminal Na(+) -dependent Pi transporter in the murine ileum and its absence is fully compensated for in adult females by a mechanism involving the bone-kidney axis. The contribution of this mechanism to the adaptive response is less apparent in adult males. © 2015 American Society for Bone and Mineral Research.
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Intestinal Depletion of NaPi-IIb/SLC34A2 in Mice: Renal and Hormonal Adaptation.
Journal of Bone and Mineral Research, 2015Co-Authors: Nati Hernando, Heini Murer, Carsten A. Wagner, Komuraiah Myakala, Fabia Simona, Thomas Knopfel, Linto Thomas, Jürg BiberAbstract:The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications. Here we report the generation of a constitutive but intestinal-specific NaPi-IIb/SLC34A2-deficient mouse model. Constitutive intestinal ablation of NaPi-IIb results in viable pups with normal growth. Homozygous mice are characterized by fecal wasting of Pi and complete absence of Na/Pi cotransport activity in BBM vesicles (BBMVs) isolated from ileum. In contrast, the urinary excretion of Pi is reduced in these animals. The plasma levels of Pi are similar in wild-type and NaPi-IIb-deficient mice. In females, the reduced phosphaturia associates with higher expression of NaPi-IIa and higher Na/Pi cotransport activity in renal BBMVs, as well as with reduced plasma levels of intact FGF-23. A similar trend is found in males. Thus, NaPi-IIb is the only luminal Na(+) -dependent Pi transporter in the murine ileum and its absence is fully compensated for in adult females by a mechanism involving the bone-kidney axis. The contribution of this mechanism to the adaptive response is less apparent in adult males. © 2015 American Society for Bone and Mineral Research.
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Phosphate transporters of the SLC20 and SLC34 families.
Molecular Aspects of Medicine, 2013Co-Authors: Ian C. Forster, Jürg Biber, Nati Hernando, 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.
Jürg Biber - One of the best experts on this subject based on the ideXlab platform.
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intestinal depletion of napi iib SLC34A2 in mice renal and hormonal adaptation
Journal of Bone and Mineral Research, 2015Co-Authors: Nati Hernando, Heini Murer, Carsten A. Wagner, Komuraiah Myakala, Fabia Simona, Thomas Knopfel, Linto Thomas, Jürg BiberAbstract:The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications. Here we report the generation of a constitutive but intestinal-specific NaPi-IIb/SLC34A2-deficient mouse model. Constitutive intestinal ablation of NaPi-IIb results in viable pups with normal growth. Homozygous mice are characterized by fecal wasting of Pi and complete absence of Na/Pi cotransport activity in BBM vesicles (BBMVs) isolated from ileum. In contrast, the urinary excretion of Pi is reduced in these animals. The plasma levels of Pi are similar in wild-type and NaPi-IIb-deficient mice. In females, the reduced phosphaturia associates with higher expression of NaPi-IIa and higher Na/Pi cotransport activity in renal BBMVs, as well as with reduced plasma levels of intact FGF-23. A similar trend is found in males. Thus, NaPi-IIb is the only luminal Na(+) -dependent Pi transporter in the murine ileum and its absence is fully compensated for in adult females by a mechanism involving the bone-kidney axis. The contribution of this mechanism to the adaptive response is less apparent in adult males. © 2015 American Society for Bone and Mineral Research.
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Intestinal Depletion of NaPi-IIb/SLC34A2 in Mice: Renal and Hormonal Adaptation.
Journal of Bone and Mineral Research, 2015Co-Authors: Nati Hernando, Heini Murer, Carsten A. Wagner, Komuraiah Myakala, Fabia Simona, Thomas Knopfel, Linto Thomas, Jürg BiberAbstract:The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications. Here we report the generation of a constitutive but intestinal-specific NaPi-IIb/SLC34A2-deficient mouse model. Constitutive intestinal ablation of NaPi-IIb results in viable pups with normal growth. Homozygous mice are characterized by fecal wasting of Pi and complete absence of Na/Pi cotransport activity in BBM vesicles (BBMVs) isolated from ileum. In contrast, the urinary excretion of Pi is reduced in these animals. The plasma levels of Pi are similar in wild-type and NaPi-IIb-deficient mice. In females, the reduced phosphaturia associates with higher expression of NaPi-IIa and higher Na/Pi cotransport activity in renal BBMVs, as well as with reduced plasma levels of intact FGF-23. A similar trend is found in males. Thus, NaPi-IIb is the only luminal Na(+) -dependent Pi transporter in the murine ileum and its absence is fully compensated for in adult females by a mechanism involving the bone-kidney axis. The contribution of this mechanism to the adaptive response is less apparent in adult males. © 2015 American Society for Bone and Mineral Research.
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The SLC34 family of sodium-dependent phosphate transporters
Pflügers Archiv: European Journal of Physiology, 2013Co-Authors: Carsten A. Wagner, Ian C. Forster, Nati Hernando, 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.
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Phosphate transporters of the SLC20 and SLC34 families.
Molecular Aspects of Medicine, 2013Co-Authors: Ian C. Forster, Jürg Biber, Nati Hernando, 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.
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Regulation of Intestinal Phosphate Transport I. Segmental expression and adaptation to low-Pi diet of the type IIb Na+-Pi cotransporter in mouse small intestine
American Journal of Physiology-gastrointestinal and Liver Physiology, 2005Co-Authors: Tamara Radanovic, Heini Murer, Carsten A. Wagner, Jürg BiberAbstract:The Na+-Pi cotransporter NaPi-IIb (SLC34A2) has been described to be involved in mouse small intestinal absorption of Pi and to be regulated by a number of hormones and metabolic factors. However, ...
Fayez K Ghishan - One of the best experts on this subject based on the ideXlab platform.
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molecular cloning functional characterization tissue distribution and chromosomal localization of a human small intestinal sodium phosphate na pi transporter SLC34A2
Genomics, 1999Co-Authors: Hua Xu, James F Collins, Fayez K GhishanAbstract:Phosphate plays a crucial role in cellular metabolism, and its homeostatic regulation in intestinal and renal epithelia is critical. Apically expressed sodium–phosphate (Na + –P i ) transporters play a critical role in this regulation. We have isolated a cDNA (HGMW-approved symbol SLC34A2) encoding a novel human small intestinal Na + –P i transporter. The cDNA is shown to be 4135 bp in length with an open reading frame that predicts a 689-amino-acid polypeptide. The putative protein has 76% homology to mouse intestinal type II Na + –P i transporter (Na/Pi-IIb) and lower homologies with renal type II Na + –P i transporters. Northern blots showed a singular transcript of 5.0 kb in human lung, small intestine, and kidney. Computer analysis suggests a protein with 11 transmembrane domains and several potential posttranslational modification sites. Functional characterization in Xenopus laevis oocytes showed that this cDNA encodes a functional Na + –P i transporter. Furthermore, the gene encoding this cDNA was mapped to human chromosome 4p15.1–p15.3 by the FISH method.
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Molecular Cloning, Functional Characterization, Tissue Distribution, and Chromosomal Localization of a Human, Small Intestinal Sodium–Phosphate (Na+–Pi) Transporter (SLC34A2) ☆
Genomics, 1999Co-Authors: Hua Xu, James F Collins, Fayez K GhishanAbstract:Phosphate plays a crucial role in cellular metabolism, and its homeostatic regulation in intestinal and renal epithelia is critical. Apically expressed sodium–phosphate (Na + –P i ) transporters play a critical role in this regulation. We have isolated a cDNA (HGMW-approved symbol SLC34A2) encoding a novel human small intestinal Na + –P i transporter. The cDNA is shown to be 4135 bp in length with an open reading frame that predicts a 689-amino-acid polypeptide. The putative protein has 76% homology to mouse intestinal type II Na + –P i transporter (Na/Pi-IIb) and lower homologies with renal type II Na + –P i transporters. Northern blots showed a singular transcript of 5.0 kb in human lung, small intestine, and kidney. Computer analysis suggests a protein with 11 transmembrane domains and several potential posttranslational modification sites. Functional characterization in Xenopus laevis oocytes showed that this cDNA encodes a functional Na + –P i transporter. Furthermore, the gene encoding this cDNA was mapped to human chromosome 4p15.1–p15.3 by the FISH method.
