Beamish, J. A. | bioRxiv Science

bioRxiv2026

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 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.

developmental biology↗

bioRxiv2023

Pax Protein Depletion in Proximal Tubules Triggers Conserved Mechanisms of Resistance to Acute Ischemic Kidney Injury and Prevents Transition to Chronic Kidney Disease

Acute kidney injury (AKI) is a common condition that lacks effective treatments. In part this shortcoming is due to an incomplete understanding of the genetic mechanisms that control pathogenesis and recovery. Pax2 and Pax8 are homologous transcription factors with overlapping functions that are critical for kidney development and are re-activated in AKI. In this report, we examined the role of Pax2 and Pax8 in recovery from ischemic AKI. We found that Pax2 and Pax8 are upregulated after severe AKI and correlate with chronic injury. Surprisingly, we then discovered that proximal-tubule-selective deletion of Pax2 and Pax8 resulted in a less severe chronic injury phenotype. This effect was mediated by protection against the acute insult, similar to preconditioning. Prior to injury, Pax2 and Pax8 mutant mice develop a unique subpopulation of S3 proximal tubule cells that display features usually seen only in acute or chronic injury. The expression signature of these cells was strongly enriched with genes associated with other mechanisms of protection against ischemic AKI including caloric restriction, hypoxic preconditioning, and female sex. Taken together, our results identify a novel role for Pax2 and Pax8 in mature proximal tubules that regulates critical genes and pathways involved in both injury response and protection from ischemic AKI. TRANSLATIONAL STATEMENTIdentifying the molecular and genetic regulators unique to the nephron that dictate vulnerability to injury and regenerative potential could lead to new therapeutic targets to treat ischemic kidney injury. Pax2 and Pax8 are two homologous nephron-specific transcription factors that are critical for kidney development and physiology. Here we report that proximal-tubule-selective depletion of Pax2 and Pax8 protects against both acute and chronic injury and induces an expression profile in the S3 proximal tubule with common features shared among diverse conditions that protect against ischemia. These findings highlight a new role for Pax proteins as potential therapeutic targets to treat AKI.

pathology↗