Abstract: FR-PO340

ErbB4 Deletion Accelerates Renal Fibrosis Following Renal Injury

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Zeng, Fenghua, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kloepfer, Lance A., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Tubulointerstitial fibrosis (TIF) is a component of chronic kidney disease (CKD) of any etiology and is the best predictor of progression toward end stage kidney disease. Mechanisms underlying the development and progression of TIF are still incompletely understood. Increased ErbB4 expression were seen in the tubular
epithelium of CKD kidneys. However, its role in the tubulointerstitial injuries remains to be determined.

Methods

ErbB4 expression was examined using immunohistochemistry in human biopsy fibrotic kidneys. Two mouse models of renal injury, unilateral ureteral obstruction (UUO) and ischemia reperfusion injury followed by uninephrectomy (IRI/UNx), were used to study the possible impact of ErbB4 deletion in renal fibrosis by comparing heart rescued ErbB4 deletion (ErbB4delht+) and wild-type (WT) mice. Renal function and pathological changes were examined.

Results

In human fibrotic kidneys, ErbB4 expression levels were inversely correlated to renal fibrosis as indicated by double immunofluorescence staining of ErbB4 and colagen I. In both UUO and IRI/UNx mouse models, expression levels of ErbB4 were elevated in the early stage of renal injury in the wild-type mice. In mice with global ErbB4 deletion except for transgenic rescue in cardiac tissue (ErbB4-/-ht+), UUO induced similar injury in proximal tubules compared to wild-type mice but more severe injury in distal nephrons. TIF was apparent earlier and was more pronounced following both UUO and IRI-UNx injuries in ErbB4-/-ht+ mice. With ErbB4 deletion, UUO injury inhibited AKT phosphorylation and increased the percentage of cells in G2/M arrest. Meanwhile, increased levels of nuclear immunostaining of YAP and increased expression of p-Smad3, snail1 and vimentin were also detected in kidneys wiith ErbB4 deletion compared to the wild-type mice.

Conclusion

In conclusion, increased expression of ErbB4 was detected in the early stages of human renal injury, whereas its level decreased with severe renal fibrosis, which is consistent with the finding that ErbB4 deletion promoted renal fibrosis in mouse injury models. Therefore, the early increased ErbB4 expression may reflect a compensatory effect to lessen tubulointerstitial injury.

Funding

  • NIDDK Support