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Abstract: FR-PO1073

IRhom2 Promotes Kidney Fibrosis Through Activation of EGFR in Fibroblasts

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Cao, Shirong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Pan, Yu, Shanghai Jiao Tong University, Shanghai, Shanghai, China
  • Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

In the kidney, tubulointerstitial fibrosis can result from incomplete recovery from acute kidney injury (AKI). Activation of the epidermal growth factor receptor (EGFR) has been implicated as a potential mediator of interstitial fibrosis. iRhom2, an inactive member of the Rhomboid intramembrane proteinase family, can regulate EGFR signaling pathway via activation of ADAM17 (TACE) and secretion of EGFR ligands, including amphiregulin and HB-EGF as well as secretion of TNF-α. The current studies were designed to investigate the potential role of iRhom2 in the development of kidney fibrosis.


iRhom2 knockout (iRhom2-/-) and WT mice (C56/Bl6, male, 8-12 weeks old) were used for all experiments. Models of kidney injury included ischemia/reperfusion (IRI) and unilateral ureteral obstruction (UUO). Kidney myeloid cells and fibroblasts/myofibroblasts were isolated with corresponding microbeads.


In the UUO model, iRhom2 mRNA expression increased in total kidney, isolated myeloid cells, and isolated kidney fibroblasts/myofibroblasts. Immunofluorescent staining confirmed iRhom2 expression in renal macrophages (F4/80+ iRhom2+ cells) and myofibroblasts (α-SMA+ iRhom2+ cells). Although the numbers of α-SMA+ cells and p-EGFR+ α-SMA+ cells were minimal under normal condition, they markedly increased after UUO for 8 days. In iRhom2-/- mice, both the numbers of α-SMA+ myofibroblasts and p-EGFR+ (indication of EGFR activation) α-SMA+ myofibroblasts decreased, with the percentage of p-EGFR expressing myofibroblasts decreasing from 43% to 17%. Quantitative Picrosirius red staining clearly showed less kidney interstitial fibrosis in iRhom2-/- mice. Four weeks after ischemic injury, iRhom2-/- mice also developed less fibrosis, as indicated by reduction in kidney profibrotic and fibrotic gene and protein expression as well as quantitative Picrosirius red staining. In addition, iRhom2-/- mice had preserved kidney function, as indicated by higher glomerular filtration rate 4 weeks after ischemic injury.


These studies provided evidence for a potential role of iRhom2 in development of kidney fibrosis in response to kidney injury, due at least in part by stimulating EGFR activation in fibroblasts/myofibroblasts. Targeting iRhom2 may provide a new strategy for prevention of kidney interstitial fibrosis.


  • NIDDK Support