FGF23-Klotho signaling axis in the kidney

Erben, Reinhold G.; Andrukhova, Olena

doi:10.1016/j.bone.2016.09.010

Cited by 130 publications

(118 citation statements)

References 83 publications

(139 reference statements)

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“…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. C) …”

Section: Sglt2i Effects On Bone Health and Mineral Metabolismmentioning

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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Section: Sglt2i Effects On Bone Health and Mineral Metabolismmentioning

confidence: 99%

Mineral and Electrolyte Disorders With SGLT2i Therapy

et al. 2019

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“…). KL acts as an obligate co‐receptor of the FGF23 receptor FGFR1 that mediates inhibition of NaPi‐2 expression in PCT cells via a mechanism involving phosphorylation of Na + /H + exchange regulatory cofactor (NHERF)‐1 (Erben and Andrukhova ). ME‐1‐mediated inhibition of EGFR may decrease KL expression in PCT, preventing FGF23‐mediated downregulation of NaPi‐2 expression, thus decreasing phosphaturia.…”

Section: Discussionmentioning

confidence: 99%

“…). Indeed, PTH can induce phosphorylation of NHERF‐1 and downregulation of NaPi‐2 without involvement of FGF23 or FGFR1/KL (Erben and Andrukhova ). However, during hypomagnesemia PTH secretion is reduced due to parathyroid gland failure (Hermans et al.…”

Section: Discussionmentioning

confidence: 99%

Antibody‐mediated inhibition of EGFR reduces phosphate excretion and induces hyperphosphatemia and mild hypomagnesemia in mice

Ortega

Dey

Gardella

et al. 2017

Physiological Reports

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Monoclonal antibody therapies targeting the EGF receptor (EGFR) frequently result in hypomagnesemia in human patients. In contrast, EGFR tyrosine kinase inhibitors do not affect Mg2+ balance in patients and only have a mild effect on Mg2+ homeostasis in rodents at elevated doses. EGF has also been shown to affect phosphate (Pi) transport in rat and rabbit proximal convoluted tubules (PCT), but evidence from studies targeting EGFR and looking at Pi excretion in whole animals is still missing. Thus, the role of EGF in regulating reabsorption of Mg2+ and/or Pi in the kidney remains controversial. Here, we inject mice with the anti‐EGFR monoclonal antibody ME‐1 for 2 weeks and observe a significant increase in serum Pi and mild hypomagnesemia, but no changes in Pi or Mg2+ excretion. In contrast, a single injection of ME‐1 resulted in hyperphosphatemia and a significant reduction in Pi excretion 2 days after treatment, while no changes in serum Mg2+ or Mg2+ excretion were observed. Dietary Mg2+ deprivation is known to trigger a rapid Mg2+ conservation response in addition to hyperphosphatemia and hyperphosphaturia. Interestingly, one dose of ME‐1 did not significantly modify the response of mice to 2 days of Mg2+ deprivation. These data show that EGFR plays a significant role in regulating Pi reabsorption in the kidney PCT, but suggest only a minor role in long‐term regulation of Mg2+ transport in the distal convoluted tubule.

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“…This role is highly conserved throughout evolution, certainly as far as zebrafish (Mangos et al, 2012) and perhaps as far as nematodes (Château et al, 2010). Through mediation of FGF23 signaling, m-KL forms part of a multi-organ regulatory mechanism that controls the levels of circulating calcium, phosphate and vitamin D (Erben and Andrukhova, 2016). Importantly, much of the kl/kl phenotype, including neuropathological and cognitive defects, can be attributed to loss of renal FGF23 signaling.…”

Section: α-Klotho and The Kidneymentioning

confidence: 99%