Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria

Dickson W.L. Wong, Wai Han Yiu, Kam Wa Chan, Ye Li, Bin Li, Sarah W.Y. Lok, Makoto M. Taketo, Peter Igarashi, Loretta Y.Y. Chan, Joseph C.K. Leung, Kar Neng Lai, Sydney C.W. Tang

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Imbalance of Wnt/β-catenin signaling in renal cells is associated with renal dysfunction, yet the precise mechanism is poorly understood. Previously we observed activated Wnt/β-catenin signaling in renal tubules during proteinuric nephropathy with an unknown net effect. Therefore, to identify the definitive role of tubular Wnt/β-catenin, we generated a novel transgenic “Tubcat” mouse conditionally expressing stabilized β-catenin specifically in renal tubules following tamoxifen administration. Four weeks after tamoxifen injection, uninephrectomized Tubcat mice displayed proteinuria and elevated blood urea nitrogen levels compared to non-transgenic mice, implying a detrimental effect of the activated signaling. This was associated with infiltration of the tubulointerstitium predominantly by M1 macrophages and overexpression of the inflammatory chemocytokines CCL-2 and RANTES. Induction of overload proteinuria by intraperitoneal injection of low-endotoxin bovine serum albumin following uninephrectomy for four weeks aggravated proteinuria and increased blood urea nitrogen levels to a significantly greater extent in Tubcat mice. Renal dysfunction correlated with the degree of M1 macrophage infiltration in the tubulointerstitium and renal cortical up-regulation of CCL-2, IL-17A, IL-1β CXCL1, and ICAM-1. There was overexpression of cortical TLR-4 and NLRP-3 in Tubcat mice, independent of bovine serum albumin injection. Finally, there was no fibrosis, activation of epithelial-mesenchymal transition or non-canonical Wnt pathways observed in the kidneys of Tubcat mice. Thus, conditional activation of renal tubular Wnt/β-catenin signaling in a novel transgenic mouse model demonstrates that this pathway enhances intrarenal inflammation via the TLR-4/NLRP-3 inflammasome axis in overload proteinuria.

Original languageEnglish (US)
Pages (from-to)1367-1383
Number of pages17
JournalKidney international
Volume93
Issue number6
DOIs
StatePublished - Jun 2018

Bibliographical note

Publisher Copyright:
© 2018 International Society of Nephrology

Keywords

  • Wnt/β-catenin
  • proteinuric nephropathy
  • renal inflammation

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