The hormetic functions of Wnt pathways in tubular injury
Elisabeth F. Gröne
Peter J. Nelson
Received: 9 May 2017 /Revised: 13 June 2017 /Accepted: 13 June 2017 /Published online: 6 July 2017
The Author(s) 2017. This article is an open access publication
Abstract Chronic tubulointerstitial damage with tubular epi-
thelial atrophy and interstitial fibrosis is the hallmark of chronic
kidney disease (CKD) and a predictor for progression of CKD.
Several experiments have now provided evidence that the
Wnt signaling pathways are significantly contributing to atrophy
and fibrosis; in contrast, it also has been shown that the Wnt
system fosters regenerative processes in acute tubular injury.
We now have demonstrated that Dickkopf 3 (DKK3) is an
agonist for canonical Wnt signaling in CKD and fosters
chronic fibrosing inflammation of the tubulointerstitial com-
partment. Genetic- and antibody-mediated inhibition of
DKK3 leads to a pronounced improvement of tubular differ-
entiation and a reduction in fibrosis.
In addition, the secreted glycoprotein DKK3 can be used as
a non-invasive urinary marker for the extent of CKD in man.
Keywords Wnt pathways
Definition of acute and chronic tubular injury
in the study of Wnts
As the effects of Wnt pathways in tubular injury will be
discussed, these actions should be put into context of the quality
and extent of epithelial injury which may be species-specific
and may not necessarily reflect the pathohistology and patho-
physiology of acute and chronic renal tubulointerstitial diseases
seen in man.
In man, acute injury of tubular epithelia can be characterized
by morphologic, biochemical, and functional means. In proxi-
mal tubules, lesions can vary from slight cytoplasmic
vacuolization and a change in brush border height to cell death.
Different degrees of loss of cell polarity and differentiation can
be associated with emergence of embryonal gene and protein
patterns. Exemplarily, vimentin—by convention assumed to be
a mesenchymal cytoskeletal protein marker—can be observed
temporarily. Once the causative factor ceases to exert its influ-
ence on injured epithelia, a regenerative process occurs which
mayleadtoa“restitutio ad integrum”, but can also result in focal
chronic atrophic and fibrotic areas of the tubulointerstitium of
the cortex and the outer medulla. Cells and matrix surrounding
the tubules exert a significant influence on the extent of injury
and its recovery. Tubulointerstitial crosstalk is a term to describe
the interaction between tubular epithelia and interstitial cells
although it obfuscates the lack of knowledge of this process.
There can be major differences between rodent models of acute
tubular injury and the morphology of acute epithelial lesions
seen in human renal biopsies.
In acute renal failure in humans, tubular epithelial injury
often occurs without significant inflammatory mononuclear
cell infiltrate in the interstitium and without necrosis/
This article is part of the special issue on Functional Anatomy of the
Kidney in Health and Disease in Pflügers Archiv—European Journal of
* Hermann-Josef Gröne
Department of Cellular and Molecular Pathology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280,
69120 Heidelberg, Germany
Clinical Biochemistry, Ludwig Maximilian University,
Munich, Bavaria, Germany
Pflugers Arch - Eur J Physiol (2017) 469:899–906