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 6

Dickkopf 3 (DKK3) is a biomarker for tubular atrophy and interstitial fibrosis in the urine of patients suffering from progressive CKD.

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Dickkopf 3 (DKK3) is a biomarker for tubular atrophy and interstitial fi...
(A) DKK3 protein levels in the urine of mice fed with adenine-enriched diet for 2, 7, 14, 21, and 28 days (n = 20), detected by ELISA. As a control, urine from mice before adenine administration was used. (B) DKK3 protein levels in the urine of healthy, young volunteers (control, n = 8) and CKD-suffering patients (n = 72), detected by ELISA. (C) Correlation of DKK3 urine levels and the respective estimated glomerular filtration rate (eGFR) of pediatric patients’ cohort samples. (D) Receiver operating characteristic (ROC) curve derived for DKK3, using a threshold of 25 ml/min/1.73 m2 for eGFR and defining the 2 patient groups as eGFR ≤25 = severe disease and eGFR >25 = nonsevere disease. AUC = 0.8815 (95% CI, 0.8056–0.9575). (E) Correlation of DKK3 urine levels and protein/creatinine levels of pediatric patients. (F) Representative images of Periodic acid–Schiff– (PAS-) and trichrome-stained renal biopsies of CKD-affected patients and related urine DKK3 concentration (scale bars: 100 μm). (G) Correlation of DKK3 urine levels and the grade of tubular atrophy (TA) in adult patients’ cohort samples. TA grades are defined as 0 = 0%–4.9% TA; 0.5 = 5%–15% TA; 1 = 15.1%–33% TA; 2 = 33.1%–66% TA; 3 = 66.1%–100% TA. (H) ROC curve derived for DKK3, using a threshold of 25% TA and defining the 2 patient groups as TA ≤25% = nonsevere disease and TA >25% = severe disease. AUC = 0.8646 (95% CI, 0.7248–1). (I) Correlation of DKK3 urine levels and the grade of interstitial fibrosis (IF) in adult patients’ cohort samples. IF grades are defined as 0 = 0%–4.9% IF; 0.5 = 5%–15% IF; 1 = 15.1%–33% IF; 2 = 33.1%–66% IF; 3 = 66.1%–100% IF. (J) ROC curve derived for DKK3, using a threshold of 25% IF and defining the 2 patient groups as IF ≤25% = nonsevere disease and IF >25% = severe disease. AUC = 0.825 (95% CI, 0.6911–0.9589). (K) Correlation of creatinine plasma levels and the grade of TA in adult patients’ cohort samples. The TA grades are defined as in G. (L) ROC curve derived for creatinine, using a threshold of 25% TA and defining the 2 patient groups as TA ≤25% = nonsevere disease and TA >25% = severe disease. AUC = 0.7622 (95% CI, 0.5939–0.9304). (M) Correlation of creatinine plasma levels and the grade of IF in adult patients’ cohort samples. The IF grades are defined as in I. (N) ROC curve derived for creatinine, using a threshold of 25% IF and defining the 2 patient groups as IF ≤25% = nonsevere disease and IF >25% = severe disease. AUC = 0.6812 (95% CI, 0.445–0.9175).