Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis
Giuseppina Federico, … , Bernd Arnold, Hermann-Josef Gröne
Giuseppina Federico, … , Bernd Arnold, Hermann-Josef Gröne
Published January 21, 2016
Citation Information: JCI Insight. 2016;1(1):e84916. https://doi.org/10.1172/jci.insight.84916.
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Research Article Immunology Nephrology

Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis

Abstract

Renal tubular atrophy and interstitial fibrosis are common hallmarks of etiologically different progressive chronic kidney diseases (CKD) that eventually result in organ failure. Even though these pathological manifestations constitute a major public health problem, diagnostic tests, as well as therapeutic options, are currently limited. Members of the dickkopf (DKK) family, DKK1 and -2, have been associated with inhibition of Wnt signaling and organ fibrosis. Here, we identify DKK3 as a stress-induced, tubular epithelia–derived, secreted glycoprotein that mediates kidney fibrosis. Genetic as well as antibody-mediated abrogation of DKK3 led to reduced tubular atrophy and decreased interstitial matrix accumulation in two mouse models of renal fibrosis. This was facilitated by an amplified, antifibrogenic, inflammatory T cell response and diminished canonical Wnt/β-catenin signaling in stressed tubular epithelial cells. Moreover, in humans, urinary DKK3 levels specifically correlated with the extent of tubular atrophy and interstitial fibrosis in different glomerular and tubulointerstitial diseases. In summary, our data suggest that DKK3 constitutes an immunosuppressive and a profibrotic epithelial protein that might serve as a potential therapeutic target and diagnostic marker in renal fibrosis.

Authors

Giuseppina Federico, Michael Meister, Daniel Mathow, Gunnar H. Heine, Gerhard Moldenhauer, Zoran V. Popovic, Viola Nordström, Annette Kopp-Schneider, Thomas Hielscher, Peter J. Nelson, Franz Schaefer, Stefan Porubsky, Danilo Fliser, Bernd Arnold, Hermann-Josef Gröne

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Figure 5

Abrogation of dickkopf 3 (DKK3) limits Wnt/β-catenin signaling in tubular epithelial cells upon unilateral ureteral obstruction.

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Abrogation of dickkopf 3 (DKK3) limits Wnt/β-catenin signaling in tubul...
(A) mRNA-seq–based gene ontology analysis of Dkk3–/– (n = 3) versus WT (n = 3) mouse kidneys 7 days after unilateral ureteral obstruction (UUO). The graph shows –logP values calculated using Benjamini-Hochberg corrected 2-tailed t test for the enrichment of a specific pathway. (B) Heatmap analysis of the expression of transcripts related to the Wnt signaling in Dkk3–/– (n = 3) versus WT (n = 3) mouse kidney 7 days after UUO. (C) Representative immunofluorescence images of kidneys of TCF/LEF:H2B-GFP (n = 4) and Dkk3–/– × TCF/LEF:H2B-GFP (n = 4) mice, stained for GFP (green)/aquaporin 1 (AQP1; red) (upper image) or GFP (green)/ aquaporin 2 (AQP2; red) (lower image) 0 (Ctrl) and 7 days after UUO (scale bars: 50 μm). White dashed line (upper right images) defines the tubular area. (D) Quantification of GFP-positive nuclei in TCF/LEF:H2B-GFP (Dkk3+/+, n = 4) and Dkk3–/– × TCF/LEF:H2B-GFP (Dkk3–/–, n = 4) mouse kidneys 7 days after UUO. (E) Representative immunofluorescence images of proximity events (red spots) between disheveled (DVL) and frizzled (FZD) in HK2 cells treated either with control siRNA or DKK3 siRNA plus either vehicle or recombinant Wnt3a protein (200 ng/ml) for 1 hour. (F) Quantification of number of proximity events per cell in HK2 cells treated either with control siRNA or DKK3 siRNA, plus either vehicle or recombinant Wnt3a protein (200 ng/ml) for 1 hour. (G) Schematic illustration of the hypothetical DKK3 function in the development of renal fibrosis. All data are shown as mean ± SEM. Statistical analysis performed using an unpaired, 2-tailed t test. *P < 0.05; **P < 0.01; ***P < 0.001.