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Abstract: FR-PO123

Megalin Deletion Prevents Long-Term Loss of Glomerular Filtration Rate After Rhabdomyolysis

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Matsushita, Katsuyuki, Oregon Health & Science University, Portland, Oregon, United States
  • McCormick, James A., Oregon Health & Science University, Portland, Oregon, United States
  • Mori, Kiyoshi, School of Pharmaceut Sci, University of Shizuoka, Shizuoka, Japan
  • Yanagita, Motoko, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States
Background

Rhabdomyolysis, caused by injury, physical training, or medication, causes acute kidney injury and can lead to chronic kidney disease. Treatment is limited to supportive care and urinary alkalization, which is controversial. No specific therapy exists, but myoglobin-induced tubular epithelial apoptosis is a mechanism. Myoglobin undergoes tubular endocytosis via megalin, therefore we hypothesized that proximal tubule-specific megalin deletion would ameliorate chronic loss of glomerular filtration rate (GFR) caused by rhabdomyolysis.

Methods

Proximal tubule-specific inducible megalin deletion mice (iMegKO, LRP2 fl/fl NDRG1-CreERT2) were generated by breeding megalin floxed mice (a gift of Professor T. Willnow, Max Delbruck Institut) with NDRG1-CreERT2 (a gift of M. Yanagita, Kyoto University). Tamoxifen (150 mg/kg body weight) was injected intraperitoneally to 7 iMegKO and 7 cre- littermate control mice (all 8-12 week-old males) for 5 days, 2 weeks before rhabdomyolysis was induced by 50% glycerol injection (6.5 ml/kg). Before glycerol and 2, 30, and 60 days after injection, glomerular filtration rate (GFR) was measured by FITC-sinistrin transcutaneous clearance. After injection, all GFR measurements were expressed as %baseline. Statistical analysis was by repeated measures 2-way ANOVA.

Results

Tamoxifen only induced deletion of megalin in cre+ mice. Megalin deletion reduced GFR (745±42mL/min/100g body weight in iMegKO vs 872±35 μL/min/100g body weight in control, P<0.05). iMegKO mice did not demonstrate reduced GFR on day 2, maintaining baseline GFR to 60 days (102% baseline, ns), whereas in controls, glycerol injection induced significant, sustained decline in GFR at 30 and 60 days (76±7% baseline, p=0.005 compared with baseline, p=0.02 compared with KO).

Conclusion

Proximal tubule-specific deletion of megalin ameliorates chronic renal functional loss caused by experimental rhabdomyolysis.

GFR loss after rhabdomyolysis is prevented by iMegKO .

Funding

  • Veterans Affairs Support