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Abstract: PO1723

Effects of Varying Mild Tubular Injury on Subsequent Glomerular Injury

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Babickova, Janka, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Tubular injury predisposes to CKD, including glomerular injury. We analyzed effects of mild tubular injury on subsequent glomerular injury.

Methods

Double transgenic, Nep25/DTR+ male and female mice (with human CD25 receptor on podocytes and Diphtheria toxin (DT) receptor on proximal tubules) received DT (25, 50, or 100ng/kg; 2x one week apart, n=5/group) to induce tubular injury, or vehicle (VEH). Uninephrectomy was done 4 wks later; 5 wks later glomerular injury was induced by LMB2 toxin (CD25 ligand) and mice were sacrificed 10 days later.

Results

In males, urinary KIM-1 was significantly higher vs VEH with all DT doses on d3 after DT injections, lowest in DT25 and similar with DT50 and DT100. KIM-1 levels were only numerically higher in DT50 and DT100 vs VEH by wk 6. Urinary NGAL was significantly increased at d3 only in DT100 vs VEH. NGAL levels normalized in all DT groups by week 6. In females, KIM-1 levels were increased by d3 with highest level with DT100. KIM-1 levels were only numerically higher vs VEH in a dose-dependent manner by wk 6. Urinary NGAL on day 3 was significantly higher in DT50 and DT100, normalized by wk 6, with numerically highest level in DT100. Males had higher levels of KIM-1 vs females at all timepoints, while NGAL showed similar levels in males and females at DT100 on d3, but higher levels in females at DT100 dose at wk 6. In males, albuminuria at sacrifice after additional podocyte injury showed numerically higher levels by 67% in DT100 vs VEH. In females, albuminuria gradually increased, with levels lower than in males in all groups. Ultrastructural analysis after podocyte injury showed similar significant foot process effacement, glomerular capillary fenestration loss and increased GBM thickness in all groups.

Conclusion

Sex differences in response to tubular injury and albuminuria were observed. Even very mild tubular injury, recovered by assessment of KIM-1 and NGAL-1 led to numerical increase in albuminuria after second hit glomerular injury in both sexes. The sex-dependent differences in KIM-1 and NGAL-1 further support differential susceptibility of nephron segments to injury in females vs males, which may play a role in glomerular sensitization to injury.

Funding

  • NIDDK Support