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Gentamicin Inhibits Ca2+ Channel TRPV5 and Induces Calciuresis Independent of the Calcium-Sensing Receptor–Claudin-14 Pathway

Wouter H. van Megen, Megan R. Beggs, Sung-Wan An, Patrícia G. Ferreira, Justin J. Lee, Matthias T. Wolf, R. Todd Alexander and Henrik Dimke
JASN March 2022, 33 (3) 547-564; DOI: https://doi.org/10.1681/ASN.2021030392
Wouter H. van Megen
1Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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Megan R. Beggs
2Department of Physiology, University of Alberta, Canada
3Women and Children's Health Institute, Alberta, Canada
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Sung-Wan An
4Department of Pediatrics, Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
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Patrícia G. Ferreira
1Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
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Justin J. Lee
2Department of Physiology, University of Alberta, Canada
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Matthias T. Wolf
4Department of Pediatrics, Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
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R. Todd Alexander
2Department of Physiology, University of Alberta, Canada
3Women and Children's Health Institute, Alberta, Canada
5Department of Pediatrics, University of Alberta, Canada
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Henrik Dimke
1Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
6Department of Nephrology, Odense University Hospital, Denmark
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Significance Statement

The antibiotic gentamicin, frequently used to treat Gram-negative bacteria infections, has significant side effects, including renal Ca2+ wasting. Gentamicin has been presumed to induce calciuresis by activating the renal Ca2+-sensing receptor, which would increase expression of the pore-blocking protein claudin-14 and reduce Ca2+ reabsorption in the thick ascending limb. However, this hypothesis has not been confirmed experimentally. Using a combination of mouse models with impaired Ca2+ reabsorption in the proximal tubule and the thick ascending limb, we show that neither acute nor chronic gentamicin administration induces calciuresis by acting on these segments. Instead, gentamicin blocks activity of the distal nephron Ca2+ channel transient receptor potential vanilloid 5 (TRPV5) and decreases calciotropic protein expression, thereby reducing distal nephron Ca2+ reabsorption. These findings illuminate the mechanism underlying gentamicin-induced urinary Ca2+ loss.

Abstract

Background Treatment with the aminoglycoside antibiotic gentamicin can be associated with severe adverse effects, including renal Ca2+ wasting. The underlying mechanism is unknown but it has been proposed to involve activation of the Ca2+-sensing receptor (CaSR) in the thick ascending limb, which would increase expression of claudin-14 (CLDN14) and limit Ca2+ reabsorption. However, no direct evidence for this hypothesis has been presented.

Methods We studied the effect of gentamicin in vivo using mouse models with impaired Ca2+ reabsorption in the proximal tubule and the thick ascending limb. We used a Cldn14 promoter luciferase reporter assay to study CaSR activation and investigated the effect of gentamicin on activity of the distal nephron Ca2+ channel transient receptor potential vanilloid 5 (TRPV5), as determined by patch clamp in HEK293 cells.

Results Gentamicin increased urinary Ca2+ excretion in wild-type mice after acute and chronic administration. This calciuretic effect was unaltered in mice with genetic CaSR overactivation and was present in furosemide-treated animals, whereas the calciuretic effect in Cldn14−/− mice and mice with impaired proximal tubular Ca2+ reabsorption (claudin-2 [CLDN2]-deficient Cldn2−/− mice) was equivalent to that of wild-type mice. In vitro, gentamicin failed to activate the CaSR. In contrast, patch clamp analysis revealed that gentamicin strongly inhibited rabbit and human TRPV5 activity and chronic gentamicin administration downregulated distal nephron Ca2+ transporters.

Conclusions Gentamicin does not cause hypercalciuria via activation of the CaSR-CLDN14 pathway or by interfering with proximal tubular CLDN2-dependent Ca2+ reabsorption. Instead, gentamicin blocks distal Ca2+ reabsorption by direct inhibition of the Ca2+ channel TRPV5. These findings offer new insights into Ca2+ wasting in patients treated with gentamicin.

  • calcium-sensing receptor
  • hypercalciuria
  • gentamicin
  • kidney tubule
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (3)
Journal of the American Society of Nephrology
Vol. 33, Issue 3
March 2022
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Gentamicin Inhibits Ca2+ Channel TRPV5 and Induces Calciuresis Independent of the Calcium-Sensing Receptor–Claudin-14 Pathway
Wouter H. van Megen, Megan R. Beggs, Sung-Wan An, Patrícia G. Ferreira, Justin J. Lee, Matthias T. Wolf, R. Todd Alexander, Henrik Dimke
JASN Mar 2022, 33 (3) 547-564; DOI: 10.1681/ASN.2021030392

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Gentamicin Inhibits Ca2+ Channel TRPV5 and Induces Calciuresis Independent of the Calcium-Sensing Receptor–Claudin-14 Pathway
Wouter H. van Megen, Megan R. Beggs, Sung-Wan An, Patrícia G. Ferreira, Justin J. Lee, Matthias T. Wolf, R. Todd Alexander, Henrik Dimke
JASN Mar 2022, 33 (3) 547-564; DOI: 10.1681/ASN.2021030392
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  • calcium-sensing receptor
  • hypercalciuria
  • gentamicin
  • kidney tubule

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