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PreprintCC BY-NC-NDbioRxiv

Megalin (LRP2), prenatal betamethasone, and injury susceptibility in the developing kidney

  • C. Nakum
  • B. Bull
  • S. Yarlagadda
  • S. Indugula
  • K. Stowers
  • K. A. VandenHeuval
  • J. T. Ference-Salo
  • J. A. Beamish
  • A. Volz
  • J. E. Robinson
  • A. Nakamura
  • L. Ding
3 more authors
  • D. K. Singh
  • B. Prasad
  • M. P. Schuh1
  1. 1Division of Nephrology and Hypertension, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University
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Abstract

Preterm infants undergo postnatal nephrogenesis and are often exposed to gentamicin (gent). Mothers at risk of preterm birth receive betamethasone (beta) to accelerate fetal lung development. Gent cytotoxicity occurs in proximal tubules (PT) after megalin (LRP2)-mediated endocytosis and accumulation. The objective of this study was to evaluate the impact of proximal tubular maturation, impacted by both age and prenatal beta, on injury susceptibility and nephron number in rats. Pups were given toxic gent dosing (100mg/kg) or saline intraperitoneal for 5 days during nephrogenesis (P0-4) or tubular maturation (P6-10). This was repeated with maternal exposure to beta to evaluate impact of beta on injury. Quantitative proteomics analysis revealed significantly higher levels of LRP2 at P10 as compared to P4, correlating with increased injury to gent exposure from P6-10 relative to P0-4. P10 pups exposed to prenatal beta had significantly more LRP2 protein relative to controls, which correlated to more injury after gent exposure at P6-10. Only those exposed to prenatal beta with P6-10 gent demonstrated ~50% nephron reduction. This study supports that tubular maturation is a critical period of vulnerability to gentamicin correlating to LRP2 protein abundance. Prenatal corticosteroids increase the severity of acute and chronic injury in this highest risk exposure group.

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Cite

BibTeXRIS
BibTeX
@misc{nakum2026megalin,
  title = {{Megalin (LRP2), prenatal betamethasone, and injury susceptibility in the developing kidney}},
  author = {C. Nakum and B. Bull and S. Yarlagadda and S. Indugula and K. Stowers and K. A. VandenHeuval and J. T. Ference-Salo and J. A. Beamish and A. Volz and J. E. Robinson and A. Nakamura and L. Ding and D. K. Singh and B. Prasad and M. P. Schuh},
  howpublished = {bioRxiv},
  year = {2026},
  month = jun,
  doi = {10.64898/2026.06.02.729064},
  url = {https://www.biorxiv.org/content/10.64898/2026.06.02.729064v2},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Megalin (LRP2), prenatal betamethasone, and injury susceptibility in the developing kidney
AU  - C. Nakum
AU  - B. Bull
AU  - S. Yarlagadda
AU  - S. Indugula
AU  - K. Stowers
AU  - K. A. VandenHeuval
AU  - J. T. Ference-Salo
AU  - J. A. Beamish
AU  - A. Volz
AU  - J. E. Robinson
AU  - A. Nakamura
AU  - L. Ding
AU  - D. K. Singh
AU  - B. Prasad
AU  - M. P. Schuh
PY  - 2026
DA  - 2026/06/02
PB  - bioRxiv
DO  - 10.64898/2026.06.02.729064
UR  - https://www.biorxiv.org/content/10.64898/2026.06.02.729064v2
AB  - Preterm infants undergo postnatal nephrogenesis and are often exposed to gentamicin (gent). Mothers at risk of preterm birth receive betamethasone (beta) to accelerate fetal lung development. Gent cytotoxicity occurs in proximal tubules (PT) after megalin (LRP2)-mediated endocytosis and accumulation. The objective of this study was to evaluate the impact of proximal tubular maturation, impacted by both age and prenatal beta, on injury susceptibility and nephron number in rats. Pups were given toxic gent dosing (100mg/kg) or saline intraperitoneal for 5 days during nephrogenesis (P0-4) or tubular maturation (P6-10). This was repeated with maternal exposure to beta to evaluate impact of beta on injury. Quantitative proteomics analysis revealed significantly higher levels of LRP2 at P10 as compared to P4, correlating with increased injury to gent exposure from P6-10 relative to P0-4. P10 pups exposed to prenatal beta had significantly more LRP2 protein relative to controls, which correlated to more injury after gent exposure at P6-10. Only those exposed to prenatal beta with P6-10 gent demonstrated ~50% nephron reduction. This study supports that tubular maturation is a critical period of vulnerability to gentamicin correlating to LRP2 protein abundance. Prenatal corticosteroids increase the severity of acute and chronic injury in this highest risk exposure group.
ER  -