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

被引：99

作者：

Federico, Giuseppina ^{[1
]}

Meister, Michael ^{[2
]}

Mathow, Daniel ^{[1
]}

Heine, Gunnar H. ^{[3
]}

Moldenhauer, Gerhard ^{[2
]}

Popovic, Zoran V. ^{[1
]}

Nordstroem, Viola ^{[1
]}

Kopp-Schneider, Annette ^{[4
]}

Hielscher, Thomas ^{[4
]}

Nelson, Peter J. ^{[5
,6
]}

Schaefer, Franz ^{[7
]}

Porubsky, Stefan ^{[1
]}

Fliser, Danilo ^{[3
]}

Arnold, Bernd ^{[2
]}

Groene, Hermann-Josef ^{[1
]}

机构：

[1] German Canc Res Ctr, Dept Cellular & Mol Pathol, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr, Dept Mol Immunol, Heidelberg, Germany

[3] Univ Saarland, Dept Internal Med Nephrol & Hypertens 4, Med Ctr, Homburg, Germany

[4] German Canc Res Ctr, Dept Biostat, Heidelberg, Germany

[5] Ludwig Maximilians Univ Munchen, Dept Internal Med, Clin Biochem Grp, Munich, Germany

[6] Ludwig Maximilians Univ Munchen, Policlin 4, Munich, Germany

[7] Heidelberg Univ, Div Pediat Nephrol, Heidelberg, Germany

来源：

JCI INSIGHT | 2016年 / 1卷 / 01期

关键词：

CD4(+) T-CELLS; NF-KAPPA-B; BETA-CATENIN; SIGNALING PATHWAYS; MOLECULAR-MECHANISMS; KIDNEY-DISEASE; EXPRESSION; PROTEINS; MICE; LYMPHOCYTES;

D O I：

10.1172/jci.insight.84916

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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/beta-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.

引用

页数：15

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