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

TitleActivated renal tubular Wnt/~β-catenin signaling triggers renal inflammation during overload proteinuria
Authors
KeywordsProteinuric nephropathy
Renal inflammatioN
Wnt/β-catenin
Issue Date2018
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ki/index.html
Citation
Kidney International, 2018, v. 93 n. 6, p. 1367-1383 How to Cite?
AbstractImbalance 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.
Persistent Identifierhttp://hdl.handle.net/10722/259364
ISSN
2017 Impact Factor: 8.429
2015 SCImago Journal Rankings: 3.181
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorWong, WLD-
dc.contributor.authorYiu, WH-
dc.contributor.authorChan, KW-
dc.contributor.authorLI, Y-
dc.contributor.authorLI, B-
dc.contributor.authorLok, SWY-
dc.contributor.authorTaketo, MM-
dc.contributor.authorIgarashi, P-
dc.contributor.authorChan, YY-
dc.contributor.authorLeung, JCK-
dc.contributor.authorLai, KN-
dc.contributor.authorTang, SCW-
dc.date.accessioned2018-09-03T04:06:11Z-
dc.date.available2018-09-03T04:06:11Z-
dc.date.issued2018-
dc.identifier.citationKidney International, 2018, v. 93 n. 6, p. 1367-1383-
dc.identifier.issn0085-2538-
dc.identifier.urihttp://hdl.handle.net/10722/259364-
dc.description.abstractImbalance 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.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ki/index.html-
dc.relation.ispartofKidney International-
dc.subjectProteinuric nephropathy-
dc.subjectRenal inflammatioN-
dc.subjectWnt/β-catenin-
dc.titleActivated renal tubular Wnt/~β-catenin signaling triggers renal inflammation during overload proteinuria-
dc.typeArticle-
dc.identifier.emailYiu, WH: whyiu@hku.hk-
dc.identifier.emailChan, KW: chriskwc@hku.hk-
dc.identifier.emailChan, YY: yychanb@hku.hk-
dc.identifier.emailLeung, JCK: jckleung@hku.hk-
dc.identifier.emailLai, KN: knlai@hku.hk-
dc.identifier.emailTang, SCW: scwtang@hku.hk-
dc.identifier.authorityLeung, JCK=rp00448-
dc.identifier.authorityLai, KN=rp00324-
dc.identifier.authorityTang, SCW=rp00480-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.kint.2017.12.017-
dc.identifier.pmid29605095-
dc.identifier.pmcidPMC5967994-
dc.identifier.hkuros288099-
dc.identifier.volume93-
dc.identifier.issue6-
dc.identifier.spage1367-
dc.identifier.epage1383-
dc.publisher.placeUnited Kingdom-

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