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Kidney Week

Abstract: PO0387

Role of Megalin and Sex in AKI-CKD Transition due to Cardiorenal Syndrome Type 1

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Funahashi, Yoshio, Oregon Health & Science University, Portland, Oregon, United States
  • Hebert, Jessica Faith, Oregon Health & Science University, Portland, Oregon, United States
  • Burfeind, Kevin G., Oregon Health & Science University, Portland, Oregon, United States
  • Munhall, Adam C., Oregon Health & Science University, Portland, Oregon, United States
  • Nickerson, Megan N., Oregon Health & Science University, Portland, Oregon, United States
  • Groat, Tahnee, Oregon Health & Science University, Portland, Oregon, United States
  • Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States
Background

Cardiorenal syndrome type 1 (CRS-1) is acute kidney injury (AKI) due to rapid worsening of cardiac function. The megalin-mediated endocytic system is an important component of renal function which may influence AKI and which likely influences development of chronic kidney injury (CKD). As part of investigating AKI-CKD transition after CRS-1, we tested whether megalin deletion affects the severity of CRS-1 and consequential CKD.

Methods

Male and female proximal tubule-specific inducible megalin deletion mice (iMegKO, LRP2 fl/fl NDRG1-CreERT2) received tamoxifen (150 mg/kg) for 5 days, 16 days before cardiac arrest and cardiopulmonary resuscitation (CA/CPR). 24 hours after CA/CPR, glomerular filtration rate (GFR), cystatin c, KIM-1 were measured and urine proteins were characterized. Immunofluorescence and immunoblotting were performed to quantify acute and chronic renal injury, fibrosis, and megalin expression.

Results

Tamoxifen only induced deletion of megalin in cre+ mice. Urine protein and urine albumin were increased by proximal tubule-specific megalin deletion, primarily low-molecular weight proteins. Specific megalin ligands including RBP-4 were elevated in the urine. At baseline, GFR of iMegKO mice was higher than control mice (p<0.001 by student’s t-test, n=11-12/group). CA/CPR variables, including time to resuscitation and epinephrine dose were not different between groups (p>0.05 by one-way Anova, n=9-13/group). Body weight-corrected urine volume at 24 hours after CA/CPR or 49 days after CA/CPR were not different between iMegKO mice and cre- littermate control mice, both in male and female groups (p>0.05 by one-way Anova; for 24h analysis, n=5-9/group, for 49day analysis, n=2-3/group). GFR at 24 hours and 49 days after CA/CPR was not different in iMegKO mice compared with littermate control mice (p>0.05 by one-way Anova; for 24h analysis, n=5-6/group, for 49day analysis, n=2/group). In female, iMegKO didn’t mediate GFR at 24 hours or 49 days after CA/CPR (p>0.05 by one-way Anova; for 24h analysis, n=2-3/group, for 49day analysis, n=3/group).

Conclusion

iMegKO causes low molecular weight proteinuria, of specific megalin ligands. GFR of iMegKO and control is different at baseline, but not different by 24h or 49days after CA/CPR in male and female.

Funding

  • Veterans Affairs Support