Activated renal tubular Wnt/ß-catenin signaling triggers renal inflammation during overload proteinuria.
Kidney Int
; 93(6): 1367-1383, 2018 06.
Article
in En
| MEDLINE
| ID: mdl-29605095
ABSTRACT
Imbalance of Wnt/ß-catenin signaling in renal cells is associated with renal dysfunction, yet the precise mechanism is poorly understood. Previously we observed activated Wnt/ß-catenin signaling in renal tubules during proteinuric nephropathy with an unknown net effect. Therefore, to identify the definitive role of tubular Wnt/ß-catenin, we generated a novel transgenic "Tubcat" mouse conditionally expressing stabilized ß-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-1ß, 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/ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proteinuria
/
Inflammation Mediators
/
Beta Catenin
/
Wnt Signaling Pathway
/
Kidney Tubules
/
Macrophages
/
Nephritis
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Kidney Int
Year:
2018
Document type:
Article
Affiliation country:
China