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 2

Antibody-mediated dickkopf 3 (DKK3) blockade ameliorates renal tubular damage and interstitial fibrosis.

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Antibody-mediated dickkopf 3 (DKK3) blockade ameliorates renal tubular d...
(A) Schematic illustration of the antibody administration protocol. Anti-DKK3 or isotype control antibody (1 mg) was administered to WT mice immediately after unilateral ureteral obstruction (UUO). Afterward, 0.5 mg of the respective antibodies was applied every third day until mice were sacrificed after 21 days. (B) Representative images of Periodic acid–Schiff–stained (PAS-stained) kidney sections from isotype (n = 13) and DKK3 antibody–treated (n = 12) mice 21 days after UUO (scale bars: 100 μm). (C) Quantification of segmental differentiated tubules in PAS-stained kidney sections of WT (n = 9), Dkk3–/– (n = 6), isotype- (n = 13), and DKK3 antibody–treated (n = 12) mice 21 days after UUO. (D) Representative images of Masson’s trichrome–stained kidney sections from isotype- (n = 13) and DKK3 antibody–treated (n = 12) mice 21 days after UUO (scale bars: 100 μm). (E) Semiquantitative analysis of renal interstitial fibrosis in Masson’s trichrome–stained kidney sections of WT (n = 9), Dkk3–/– (n = 6), isotype- (n = 13), and DKK3 antibody–treated (n = 12) mice 21 days after UUO. (F) Representative CD3 IHC of kidneys of DKK3 antibody–injected (n = 6) and isotype antibody–injected (n = 6) WT mice 21 days after UUO (Scale bars: 100 μm) (left panel). Quantification of CD3+ cells per high power field (HPF, ×40) of kidney of DKK3 antibody–injected (n = 6) and isotype antibody–injected (n = 6) WT mice 21 days after UUO (right panel). All data are shown as mean ± SEM. Statistical analysis performed using Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001.