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

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 LRP2-mediated endocytosis. 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. Pups were given toxic gent dosing (100mg/kg) or saline intraperitoneal x 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. Proteomic analyses identified non-monotonic increased LRP2 protein abundance at P10, correlating with increased injury to gent exposure from P6-10 relative to P0-4. P10 pups exposed to prenatal beta had significantly more LRP2 relative to controls, which correlated to more injury after gent exposure at P6-P10. 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 expression. Prenatal corticosteroids increase the severity of acute and chronic injury in this highest risk exposure group.