Kidney Week

Abstract: TH-OR02

The Epidermal Growth Factor Receptor Is an Essential Mediator of Interstitial Fibrosis Development Following AKI

Session Information

• AKI Mechanisms: Cellular and Organ Cross-Talk
  November 02, 2023 | Location: Room 118, Pennsylvania Convention Center
  Abstract Time: 04:39 PM - 04:48 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Cao, Shirong, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Shirong Cao, MD, PhD

• Pan, Yu, Vanderbilt University Medical Center, Nashville, United States

Yu Pan,

• Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ming-Zhi Zhang,

• Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Raymond C. Harris,

Background

In the kidney, tubulointerstitial fibrosis can result from incomplete recovery from acute kidney injury (AKI), toxic injury or other inflammatory insults. Activation of the Epidermal Growth Factor Receptor (EGFR) has been implicated as a potential mediator of interstitial fibrosis but underlying mechanisms of EGFR’s actions have not been previously addressed.

Methods

To delete EGFR selectively in the fibroblast/pericyte population, we generated PDGFRβ-Cre/ERT2; mCherry (WT) and PDGFRβ-Cre/ERT2; mCherry; EGFR^f/f (FibEGFR-/-) mice. Models of acute kidney injury included ischemia/reperfusion, UUO and folate and adenine nephropathy. In vitro studies utilized immortalized mouse fibroblasts.

Results

In all models of acute injury, FibEGFR-/- mice developed less tubulointerstitial fibrosis and isolated fibroblasts had decreased collagen mRNA expression. Fibroblast EGFR expression played an essential role in fibroblast migration and proliferation after injury. In cultured mouse fibroblast cells, EGFR activation induced proliferation but decreased expression of SMAD3 and myofibroblast markers. TGF-ß did not induce proliferation but reversed EGFR’s inhibition and stimulated myofibroblast differentiation. SnRNAseq confirmed decreased markers of fibroblast proliferation and cell motility and numbers of myofibroblasts in FibEGFR-/- mice.

Conclusion

These studies provided evidence for a heretofore undescribed and important role for EGFR in kidney fibroblasts and pericytes as a specific initiator of interstitial fibrosis in response to kidney injury by stimulating pericyte/fibroblast migration and proliferation.

Funding

• NIDDK Support