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 4

TECs are the predominant source of profibrotic dickkopf 3 (DKK3) in the kidney.

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TECs are the predominant source of profibrotic dickkopf 3 (DKK3) in the ...
(A) Representative images of Periodic acid–Schiff–stained (PAS-stained) (upper panel) and Masson’s trichrome–stained (lower panel) kidney sections of WT, Rag2–/–, and Rag2–/– mice injected with WT or Dkk3–/– spleen–derived T cells 21 days after unilateral ureteral obstruction (UUO). Each mouse was injected i.p. with 3 × 107 isolated T cells 2 days before surgery (scale bars: 100 μm). (B) Quantification of renal segmental differentiated tubules in PAS-stained kidney sections of WT (n = 10), Rag2–/– (n = 11), and Rag2–/– mice injected with WT (n = 10) or Dkk3–/– spleen–derived (n = 10) T cells 21 days after UUO. (C) Semiquantitative analysis of renal interstitial fibrosis in Masson’s trichrome–stained kidney sections of WT (n = 9), Rag2–/– (n = 11), and Rag2–/– mice injected with WT- (n = 11), or Dkk3–/–-derived (n = 11) T cells, 21 days after UUO. (D) Representative ex vivo bioluminescence image of Dkk3-LCh mouse kidneys 0, 2, 7, and 21 days after UUO (n = 3). (E) Relative Dkk3 mRNA expression in mice at postnatal days 1, 7, 14, 16, and 20, as well as 8 weeks after birth. (F) Representative immunofluorescence images of Dkk3-LCh mouse kidneys 0 (Ctrl, n = 4) and 7 days after UUO (n = 4), stained for mCherry (red)/aquaporin 1 (AQP1, green) (upper panel) or mCherry (red)/aquaporin 2 (AQP2, green). (G) Representative images of kidney of PAS-stained kidney sections of Dkk3fl/fl (n = 7) and Dkk3fl/flPax8Cre (n = 8) mice 0 and 21 days after UUO (scale bars: 100 μm). (H) Quantification of renal segmental differentiated tubules in PAS-stained kidney sections of WT (n = 4), Dkk3–/– (n = 4), Dkk3fl/fl (n = 7), and Dkk3fl/flPax8Cre (n = 8) mice 21 days after UUO. (I) Representative images of Masson’s trichrome–stained kidney sections of Dkk3fl/fl (n = 9) and Dkk3fl/flPax8Cre (n = 9) mice 21 days after UUO (Scale bars: 100 μm). (J) Semiquantitative analysis of renal interstitial fibrosis in Masson’s trichrome–stained kidney sections of WT (n = 4), Dkk3–/– (n = 4), Dkk3fl/fl (n = 9), and Dkk3fl/flPax8Cre (n = 9) mice 21 days after UUO. All data are shown as mean ± SEM. Statistical analysis performed using Mann-Whitney U test. *P < 0.05; **P < 0.01.