Abstract: TH-PO306

NHERF1 Deficiency Increases Susceptibility to Cisplatin-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Bushau, Adrienne M., University of Louisville, Louisville, Kentucky, United States
  • Lederer, Eleanor D., University of Louisville; Robley Rex VA Medical Center, Louisville, Kentucky, United States
  • Conklin, Caryl, University of Louisville, Louisville, Kentucky, United States
  • Barati, Michelle T., University of Louisville, Louisville, Kentucky, United States
  • Coventry, Susan C., University of Louisville, Louisville, Kentucky, United States
  • Dupre, Tess, University of Louisville, Louisville, Kentucky, United States
  • Siskind, Leah J., University of Louisville, Louisville, Kentucky, United States
  • Brier, Michael E., University of Louisville, Louisville, Kentucky, United States
  • Khundmiri, Syed J., Howard University College of Medicine, Washington, District of Columbia, United States
  • Gagnon, Kenneth, University of Louisville, Louisville, Kentucky, United States
Background

Acute kidney injury (AKI) develops in 30% of patients who receive cisplatin (CIS), a widely used chemotherapeutic agent. We have demonstrated that NHERF1 deficiency results in differences in mitochondrial protein expression and function. We hypothesize that NHERF1-deficiency increases susceptibility to AKI through an underlying metabolic stress.

Methods

To test this hypothesis, we treated 2 month old male and female wild type (WT) C57BL/6 and NHERF1 knock out (KO) mice with vehicle or CIS (20 mg/kg dose IP) and euthanized after 72 hours. Blood was collected for blood urea nitrogen (BUN) levels. Kidneys were harvested for histology, TUNEL assay, RT-qPCR of Kidney Injury Molecule-1 (KIM-1), and Western Blot for eIF2α, GRP78, and AMPK.

Results

Significantly greater severity of injury was seen in CIS treated NHERF1 KO mice compared to WT mice as demonstrated by semi-quantitative injury score (p<0.001) and by BUN levels (WT 97.8 mg/dL +/- 10.01 vs KO 151.8 mg/dL +/- 17.2) (p<0.05). KIM-1 mRNA expression was significantly increased in both CIS treated WT (2063.7 fold control +/- 864.4) and NHERF1 KO mice (3802.1 +/- 2132.0) (p<0.05) in comparison to vehicle treated mice. TUNEL assay analysis showed significant increases in both NHERF1 KO (12.5 no. nuclei/ no. visual fields +/- 3.2) and WT (10.3 +/- 1.4) CIS treated mice (p<0.001) in comparison to vehicle treated mice. Neither KIM-1 expression nor apoptosis differed between CIS treated WT and NHERF1 KO mice. There was no difference in expression of GRP78 and p-eIF2α between WT and NHERF1 KO mice or in proximal tubule cell expression of pAMPK. There were no significant gender differences found between WT and NHERF1 KO mice for any of the measured parameters.

Conclusion

We conclude that NHERF1-deficient mice show an increase in susceptibility to CIS-induced AKI that is not due to an underlying increase in ER stress or a decrease in cell energy levels.

Funding

  • Veterans Affairs Support