Abstract: TH-PO310

Worsened Renal Fibrosis in Kras4bG12D Lung Adenocarcinoma-Bearing Mice Treated with Repeated Dosing of Cisplatin May Be EGFR-Mediated

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Sharp, Cierra, University of Louisville, Louisville, Kentucky, United States
  • Doll, Mark A., University of Louisville, Louisville, Kentucky, United States
  • Dupre, Tess, University of Louisville, Louisville, Kentucky, United States
  • Beverly, Levi J., University Of Louisville, Louisville, Kentucky, United States
  • Siskind, Leah J., University of Louisville, Louisville, Kentucky, United States
Background

Cisplatin (CDDP) is a first choice therapy for many solid cancers, but 30% of patients develop nephrotoxicity leading to acute kidney injury (AKI). AKI is defined as the rapid loss of renal function, marked by an increased mortality rate. Recent large-scale, longitudinal studies have indicated that AKI can progress to chronic kidney disease (CKD), which also has an increased mortality rate. Currently, there are no therapeutic interventions for AKI or CKD sustained from CDDP treatment. This may be due to the fact that the mouse model used to study CDDP AKI utilizes non cancer mice that are treated with one, high dose of CDDP leading to death 3-4 days after injection. Clinically, only cancer patients receive CDDP, and it is administered in low doses over an extended period of time to curtail CDDP nephrotoxicity.

Methods

We optimized a repeated dosing model of CDDP (7 mg/kg 1x/wk for 4wks), which induces fibrosis indicative of CKD. To incorporate cancer into our model, we utilized a Kras4bG12D transgenic mouse that develops lung adenocarcinoma within 6 months, and treated non cancer and cancer mice with repeated CDDP dosing.

Results

CDDP treated cancer mice had significantly decreased survival (25%) compared to CDDP treated non cancer mice. In urine, NGAL levels in CDDP treated cancer mice increased after Dose 1 (34.9 pg/ml) and Dose 2 (51.5 pg/ml), but not in CDDP treated non cancer mice. CDDP treated cancer mice had significantly worsened fibrosis as indicated by Sirius red (SR) staining (25.4% SR +), levels of myofibroblasts (α-SMA IHC; 4.6% +), and TGFβ protein levels as compared to CDDP treated non cancer mice (11.6% SR +, 2.2% α-SMA +). We hypothesized that CDDP treated cancer mice have worsened fibrosis due to the activation of different pathways involved in renal fibrosis. Indeed, CDDP treated cancer mice had increased EGFR and pEGFR Y1068 protein levels. The role of EGFR was further supported by differential activation of downstream signaling pathways in these mice (JNK and NFκB).

Conclusion

These data suggest that worsened renal outcomes in CDDP treated cancer mice may be EGFR-mediated, and that targeting EGFR may prevent renal fibrosis.

Funding

  • NIDDK Support