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

JCI Insight. 2016 Jan 21;1(1):e84916. doi: 10.1172/jci.insight.84916.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Atrophy
  • Fibrosis
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Kidney / pathology*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology*
  • Kidney Tubules / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nephritis, Interstitial / metabolism
  • Nephritis, Interstitial / pathology
  • Renal Insufficiency, Chronic / metabolism
  • Renal Insufficiency, Chronic / pathology*
  • Wnt Signaling Pathway

Substances

  • Adaptor Proteins, Signal Transducing
  • Dkk3 protein, mouse
  • Intercellular Signaling Peptides and Proteins