A model of calcium transport and regulation in the proximal tubule

Edwards, Aurélie; Bonny, Olivier

doi:10.1152/ajprenal.00129.2018

Cited by 29 publications

(28 citation statements)

References 63 publications

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“…Theoretical mathematical modeling of Ca+ reabsorption in the renal proximal tubule predicts that SGLT2 blockade in the PT should contribute to hypercalciuria. 360 Consistent with this concept, canagliflozin-treated diabetic mice (~10-20 mg/kg/day dose) exhibit persistently increased urine calcium excretion, along with increased serum FGF23 concentration, and biomarker evidence of bone resorption, despite a significant improvement in glycemic control compared with their untreated diabetic counterparts. 357,361 Increased urinary calcium excretion has also been reported in rats exposed to a supra-physiological dose of canagliflozin (100 mg/kg/day), 362,363 but this was jointly attributed to off-target effects, via SGLT1, to increase intestinal calcium absorption.…”

Section: Skeletal Effects: Clinical Investigation and Fracture Riskmentioning

confidence: 82%

“…When examined systemically, either pharmacologic or genetic inhibition of SGLT2 function appears to result in some disruption of bone mineral homeostasis in animal models. Theoretical mathematical modeling of Ca+ reabsorption in the renal proximal tubule predicts that SGLT2 blockade in the PT should contribute to hypercalciuria . Consistent with this concept, canagliflozin‐treated diabetic mice (~10‐20 mg/kg/day dose) exhibit persistently increased urine calcium excretion, along with increased serum FGF23 concentration, and biomarker evidence of bone resorption, despite a significant improvement in glycemic control compared with their untreated diabetic counterparts .…”

Section: Drugs and Bonementioning

confidence: 87%

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Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Skeletal Effects: Clinical Investigation and Fracture Riskmentioning

confidence: 82%

Section: Drugs and Bonementioning

confidence: 87%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…These findings were quite unexpected in light of the increased urinary calcium reported in rats and mice treated with SGLT2is . Currently, it is unknown whether urinary calcium results from a direct effect on proximal Ca 2+ reabsorption or from glucose‐induced osmotic diuresis .…”

Section: Sglt2i Effects On Bone Health and Mineral Metabolismmentioning

confidence: 97%

“…(53) These findings were quite unexpected in light of the increased urinary calcium reported in rats and mice treated with SGLT2is. (54,55) Currently, it is unknown whether urinary calcium results from a direct effect on proximal Ca 2+ reabsorption or from glucoseinduced osmotic diuresis. (54,55) However, increased urinary calcium may be regarded as a further potential trigger for both PTH and FGF23 secretion because animal data suggest that these two phosphaturic hormones also act as calcium-conserving hormones in the distal nephron (Fig.…”

Section: Effects Of Sglt2is On Bone Health and Mineral Metabolism Indmentioning

confidence: 99%

Mineral and Electrolyte Disorders With SGLT2i Therapy

et al. 2019

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The newly developed sodium‐glucose cotransporter 2 inhibitors (SGLT2is) effectively modulate glucose metabolism in diabetes. Although clinical data suggest that SGLT2is (empagliflozin, dapagliflozin, ertugliflozin, canagliflozin, ipragliflozin) are safe and protect against renal and cardiovascular events, very little attention has been dedicated to the effects of these compounds on different electrolytes. As with other antidiabetic compounds, some effects on water and electrolytes balance have been documented. Although the natriuretic effect and osmotic diuresis are expected with SGLT2is, these compounds may also modulate urinary potassium, magnesium, phosphate, and calcium excretion. Notably, they have had no effect on plasma sodium levels and promoted only small increases in serum potassium and magnesium concentrations in clinical trials. Moreover, SGLT2is may induce an increase in serum phosphate, FGF‐23, and PTH; reduce 1,25‐dihydroxyvitamin D; and generate normal serum calcium. Some published and preliminary reports, as well as unconfirmed reports have suggested an association with bone fractures. Some homeostasis perturbations are transient, whereas others may persist, suggesting that the administration of SGLT2is may affect electrolyte balances in exposed subjects. Although current evidence supports their safety, additional efforts are needed to elucidate the long‐term impact of these compounds on chronic kidney disease, mineral metabolism, and bone health. Indeed, the limited follow‐up studies and the heterogeneity of the case‐mix of different randomized controlled trials preclude a definitive answer on the impact of these compounds on long‐term outcomes such as the risk of bone fracture. Here we review the current understanding of the mechanisms involved in electrolyte handling and the available data on the clinical implications of electrolytes and mineral metabolism perturbations induced by SGLT2i administration. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…The majority, approximately two-thirds of filtered calcium, is reabsorbed by the proximal tubule [1]. This occurs via a paracellular route, primarily driven by the reabsorption of water from the proximal tubule [2][3][4][5][6]. A failure to reabsorb calcium from the proximal tubule has been implicated in the pathogenesis of kidney stone formation [7].…”

Section: Introductionmentioning

confidence: 99%

Claudin-12 Knockout Mice Demonstrate Reduced Proximal Tubule Calcium Permeability

Plain

Pan

O’Neill

et al. 2020

IJMS

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The renal proximal tubule (PT) is responsible for the reabsorption of approximately 65% of filtered calcium, primarily via a paracellular pathway. However, which protein(s) contribute this paracellular calcium pore is not known. The claudin family of tight junction proteins confers permeability properties to an epithelium. Claudin-12 is expressed in the kidney and when overexpressed in cell culture contributes paracellular calcium permeability (PCa). We therefore examined claudin-12 renal localization and its contribution to tubular paracellular calcium permeability. Claudin-12 null mice (KO) were generated by replacing the single coding exon with β-galactosidase from Escherichia coli. X-gal staining revealed that claudin-12 promoter activity colocalized with aquaporin-1, consistent with the expression in the PT. PTs were microperfused ex vivo and PCa was measured. PCa in PTs from KO mice was significantly reduced compared with WT mice. However, urinary calcium excretion was not different between genotypes, including those on different calcium containing diets. To assess downstream compensation, we examined renal mRNA expression. Claudin-14 expression, a blocker of PCa in the thick ascending limb (TAL), was reduced in the kidney of KO animals. Thus, claudin-12 is expressed in the PT, where it confers paracellular calcium permeability. In the absence of claudin-12, reduced claudin-14 expression in the TAL may compensate for reduced PT calcium reabsorption.

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A model of calcium transport and regulation in the proximal tubule

Cited by 29 publications

References 63 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

Mineral and Electrolyte Disorders With SGLT2i Therapy

Claudin-12 Knockout Mice Demonstrate Reduced Proximal Tubule Calcium Permeability

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