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Kidney Week

Abstract: PO0351

Role of Collagen Receptors in Radiation-Induced Nephrotoxicity

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Ahmad, Anis, University of Miami School of Medicine, Miami, Florida, United States
  • Afaghani, Jumana, University of Miami School of Medicine, Miami, Florida, United States
  • Shi, Junwei, University of Miami School of Medicine, Miami, Florida, United States
  • Ansari, Saba, University of Miami School of Medicine, Miami, Florida, United States
  • Kim, Jin Ju, University of Miami School of Medicine, Miami, Florida, United States
  • Shi, Yan, University of Miami School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States
  • Pollack, Alan, University of Miami School of Medicine, Miami, Florida, United States
  • Zeidan, Youssef, American University of Beirut (AUB) School of Medicine, Beirut, Beirut, Lebanon
  • Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
  • Marples, Brian, University of Miami School of Medicine, Miami, Florida, United States

Group or Team Name

  • Radiation Oncology
Background

Radiation therapy represents a severe late complication for cancer patients and induces radiation nephropathy (RN). Collagen receptors Discoidin domain receptor 1 (DDR1) and integrin α2 are involved in the pathogenesis of renal fibrosis. However, the mechanisms is largely unknown. We hypothesized that radiation therapy (RT)-induced collagen I accumulation in podocytes activates DDR1, integrin α2, and matrix metalloproteinases (MMPs) signaling leading to changes in the laminin and collagen homeostasis in GBM thus inducing RN.

Methods

10–14-weeks old C57BL/6 male and female mice kidneys received a single dose (SD) 4Gy, 10Gy, and 14Gy or fractionated dose (FD) 6Gyx5 and 2Gyx24 X-irradiation. Kidney function parameters (estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR), serum BUN and creatinine), histopathological changes (determined by H&E, Periodic Acid-Schiff (PAS), Picrosirius red (PSR)), gene expression analysis (by nanostring), ultrastructural changes (by transmission electron microscopy (TEM), were measured at 10- and 20-weeks post-SD and FD.

Results

IHC and nanostring data showed a significant upregulation of Col I, pDDR1, and integrin α2 expression (p<0.001) and reduction in integrin α1 (p<0.001) in kidney cortices 10 and 20 weeks post-SD and FD. Western blot and gene expression analysis showed that several MMPs expression increased significantly in a dose and time-dependent manner in cultured human podocytes and mouse kidney cortex post-RT. Significant reductions were seen in collagen type IV (Col4A3, Col4A4, Col4A5), laminin α5β2γ1 (LM-521) and a substantial increase in the expression of collagen type I (Col1A1, Col1A2), collagen type IV (Col4A1, Col4A2), laminin α1β1γ1 (LM-111) and laminin α2β1γ1 (LM-211) in radiated mice kidney cortex (p<0.001). TEM data demonstrated time and dose-dependent increases in GBM thickness and foot process width (p<0.001). Significant increases in fibrosis (PSR), mesangial expansion (PAS), ACR in association with decreased podocyte number and eGFR 20 weeks post SD and FD were observed.

Conclusion

Our data suggest that targeting collagen receptors (DDR1 and integrin α2) with specific small molecule inhibitors and genetic or pharmacological induction of integrin α3 may prevent the RN.

Funding

  • Other NIH Support