ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0407

Noncanonical Wnt5a/CD146 Signaling Drives Renal Fibrosis by Activating Transcriptional Factor Snail in AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Xiaomei, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Wen, Jiejun, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Jia, Junjie, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Zhang, Qunzi, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Zhou, Ting, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Fan, Ying, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Wang, Niansong, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
Background

Acute kidney injury (AKI) with severe and persistent kidney cell injury will more likely progress to permanent damage, progressive fibrosis and chronic kidney disease (CKD). However, the exact cellular and molecular mechanisms mediating the progression of AKI to CKD remain incompletely understood. We recently reported that Wnt5a promotes renal tubular inflammation in diabetic nephropathy by binding to CD146 through noncanonical Wnt signaling. Snail, which expressed in the precursors of the renal epithelial cells, can induce partial epithelial-to-mesenchymal transition and drive renal fibrosis in mice. Here, we investigated whether modulation of Wnt5a expression during AKI would contribute to the progression to CKD.

Methods

To examine whether Wnt5a mediated CD146/JNK pathway was involved in AKI, we determined the expression of Wnt5a and CD146 in the kidneys of AKI patients. Wnt5a knockdown mice underwent either unilateral ureteral obstruction (UUO) or ischemia reperfusion injury (IRI) was established to assess whether the loss of Wnt5a attenuated renal injury. In vitro, HK-2 proximal tubule cells were subjected to oxygen glucose deprivation (OGD) to mimic the ischemia-reperfusion injury. More over, HK-2 cells were transfected a wnt5a small interfering RNA (siRNA) to reduce the expression of Wnt5a to further confirm the role of Wnt5a/CD146 signaling in the kidney injury.

Results

Increased expression of Wnt5a and CD146 were found in the kidney sections of patients with AKI, which was associated with the severity of kidney injury and the progression to CKD. In an Wnt5a-knockdown mouse model subjected to UUO or IRI, Wnt5a ablation significantly ameliorated kidney cell injury and renal fibrosis development. Mechanistically, Wnt5a promoted the phosphorylation of JNK and the activation of snail in UUO and IRI models. Silencing Wnt5a with small interfering RNA (siRNA) attenuated the activation Wnt5a/CD146 signaling and the expression of snail in HK-2 cells with oxygen glucose deprivation (OGD).

Conclusion

Together, our data suggest that noncanonical Wnt5a/CD146 signaling may be an important determinant in the severity of AKI. Through the activation of snail, it drives the renal fibrosis and promotes the progression to CKD.

Funding

  • Government Support – Non-U.S.