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Abstract: PO0396

Myeloid Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) Protects Against Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Cao, Shirong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Pan, Yu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Epidermal growth factor receptor (EGFR) activation plays an important role to mediate recovery of epithelial integrity following ischemic acute kidney injury (AKI) and subsequent development of interstitial fibrosis when recovery is incomplete. EGFR can be activated by a family of ligands. The ligand responsible for EGFR activation after AKI has not been previously identified. In response to various stimuli, EGFR can be transactivated by its ligand, HB-EGF. The present study examined the potential role of myeloid HB-EGF in recovery from ischemic AKI and subsequent development of fibrosis.

Methods

Wild type (WT, HB-EGFf/f) or LysM-Cre; HB-EGFf/f (myeloid HB-EGF-/-) mice (male, 8 weeks old, C57BL/J background) were uninephrectomized, immediately followed by unilateral ischemia-reperfusion with renal pedicle clamping for 31.5 min. Mice were sacrificed at different time points after ischemic AKI. Renal myeloid cells were isolated with a mixture of CD11b and CD11c microbeads.

Results

Compared to WT mice, LysM-Cre; HB-EGFf/f mice had delayed functional recovery after ischemic AKI. At 28 days after AKI, myeloid HB-EGF-/- mice had more severe persistent kidney damage, indicated by higher KIM-1 mRNA and protein levels. Myeloid HB-EGF-/- mice also had more renal immune cell infiltration, including macrophages, neutrophils, and lymphocytes. The myeloid HB-EGF-/- mice exhibited more renal fibrosis, as indicated by quantitative Sirius red and Masson’s Trichrome staining and increased mRNA and protein levels of profibrotic and fibrotic components including α-SMA, collagen I, collagen IV, IL-11, fibronectin, and PDGFRβ. The myeloid HB-EGF-/- mice also had increased renal ER stress as indicated by increased CHOP. In renal myeloid cells from WT mice, HB-EGF mRNA levels were increased by 10 fold at 2 h after ischemic AKI. Immunofluorescent staining demonstrated increased HB-EGF expression in myeloid cells and increased phosphor-EGFR in the proximal tubule epithelial cells.

Conclusion

Early HB-EGF upregulation in myeloid cells in response to ischemic injury may promote functional and structural recovery after ischemic AKI, possibly due to stimulation of epithelial cell proliferation via EGFR activation.

Funding

  • NIDDK Support