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

doi:10.1016/j.kint.2017.12.017

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

Medicine - Renal and Hypertension Division

Research output: Contribution to journal › Article › peer-review

50 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 language	English (US)
Pages (from-to)	1367-1383
Number of pages	17
Journal	Kidney international
Volume	93
Issue number	6
DOIs	https://doi.org/10.1016/j.kint.2017.12.017
State	Published - Jun 2018

Bibliographical note

Funding Information:
This study is supported by the National Natural Science Fund (NSFC) of China (grant no. 81570647) and by donations from Mrs. Rita T. Liu SBS of L & T Charitable Foundation Ltd. and Indo Café and Mr. Winston Leung. WHY is supported by an Endowment Fund established for the Yu Professorship in Nephrology awarded to SCWT and a donation from Mr. K.K. Chan of Chi Lee Cement and Building Materials Co. Ltd., the Hong Kong Concrete Co. Ltd., and the Continental Cement and Gypsum Co. Ltd. We thank Prof. Peter Igarashi, the University of Texas Southwestern O'Brien Kidney Research Core Center (grant nos. NIHP30DK079328 and R37DK042921), Institute of Genetics and Molecular and Cellular Biology, and Dr. Pierre Chambon for providing the Ksp-CreER T2 mouse strain. We are also grateful to Prof. Makoto Mark Taketo from Kyoto University for providing the Catnb lox(ex3)/lox(ex3) mice. Part of the results from this study was presented in abstract form at the American Society of Nephrology Kidney Week, 2017, New Orleans, LA.

Publisher Copyright:
© 2018 International Society of Nephrology

Keywords

Wnt/β-catenin
proteinuric nephropathy
renal inflammation

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10.1016/j.kint.2017.12.017

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967994

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title = "Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria",

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.",

keywords = "Wnt/β-catenin, proteinuric nephropathy, renal inflammation",

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

note = "Funding Information: This study is supported by the National Natural Science Fund (NSFC) of China (grant no. 81570647) and by donations from Mrs. Rita T. Liu SBS of L & T Charitable Foundation Ltd. and Indo Caf{\'e} and Mr. Winston Leung. WHY is supported by an Endowment Fund established for the Yu Professorship in Nephrology awarded to SCWT and a donation from Mr. K.K. Chan of Chi Lee Cement and Building Materials Co. Ltd., the Hong Kong Concrete Co. Ltd., and the Continental Cement and Gypsum Co. Ltd. We thank Prof. Peter Igarashi, the University of Texas Southwestern O'Brien Kidney Research Core Center (grant nos. NIHP30DK079328 and R37DK042921), Institute of Genetics and Molecular and Cellular Biology, and Dr. Pierre Chambon for providing the Ksp-CreER T2 mouse strain. We are also grateful to Prof. Makoto Mark Taketo from Kyoto University for providing the Catnb lox(ex3)/lox(ex3) mice. Part of the results from this study was presented in abstract form at the American Society of Nephrology Kidney Week, 2017, New Orleans, LA. Publisher Copyright: {\textcopyright} 2018 International Society of Nephrology",

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AU - Li, Bin

AU - Lok, Sarah W.Y.

AU - Taketo, Makoto M.

AU - Igarashi, Peter

AU - Chan, Loretta Y.Y.

AU - Leung, Joseph C.K.

AU - Lai, Kar Neng

AU - Tang, Sydney C.W.

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N2 - 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.

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

Abstract

Bibliographical note

Keywords

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