Wnt signaling in kidney: the initiator or terminator?

Abstract

The kidney is a key organ in the human body that excretes toxins and sustains the water–electrolyte balance. During embryonic development and disease progression, the kidney undergoes enormous changes in macrostructure, accompanied by a variety of microstructural histological changes, such as glomerular formation and sclerosis, tubule elongation and atrophy, interstitial establishment, and fibrosis progression. All of these rely on the frequent occurrence of cell death and growth. Notably, to overcome disease, some cells regenerate through self-repair or progenitor cell differentiation. However, the signaling mechanisms underlying kidney development and regeneration have not been elucidated. Recently, Wnt signaling has been noted to play an important role. Although it is a well-known developmental signal, the role of Wnt signaling in kidney development and regeneration is not well recognized. In this review, we review the role of Wnt signaling in kidney embryonic development, tissue repair, cell division, and progenitor cell differentiation after injury. Moreover, we briefly highlight advances in our understanding of the pathogenic mechanisms of Wnt signaling in mediating cellular senescence in kidney parenchymal and stem cells, an irreversible arrest of cell proliferation blocking tissue repair and regeneration. We also highlight the therapeutic targets of Wnt signaling in kidney diseases and provide important clues for clinical strategies.

Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney

“…Accordingly, Wnt signalling is a key activator of EMT in conditions of injury [ 85 ]. Moreover, with evidence that Wnt/β-catenin signalling promotes the expression of numerous genes, including fibronectin, FSP1, Snail1, MMP7 and cyclin D1, it is not surprising that attenuation of this signalling cascade is associated with improved renal function, reduced EMT [ 86 ] and diminished inflammation [ 87 ] and fibrosis [ 80 , 88 ]. Consequently, it could, in part, account for the TGFβ1-induced increased expression and secretion of extracellular matrix proteins ( Figure 5 ), proinflammatory cytokines and chemokines observed in this study ( Figure 6 and Figure 7 ).…”

Cannabinoid receptor 2 plays a central role in renal tubular mitochondrial dysfunction and kidney ageing

“…Wnt/β‐catenin signalling is a conserved development pathway, 33 and however, it is reactive in multiple kinds of kidney diseases 34 . Interestingly, we have found that it is also overactivated in aged kidneys 6 .…”

“…Wnt/β-catenin signalling is a conserved development pathway, 33 and however, it is reactive in multiple kinds of kidney diseases. 34 Interestingly, we have found that it is also overactivated in aged kidneys. 6 The activation of β-catenin is accompanied by the loss of mito- could be activated by Wnt-triggered inhibition on its degradation 35 and also could be stimulated by GPCR-induced signal wave.…”

“…Wnt/β‐catenin signalling is a conserved development pathway, 33 and however, it is reactive in multiple kinds of kidney diseases. 34 Interestingly, we have found that it is also overactivated in aged kidneys. 6 The activation of β‐catenin is accompanied by the loss of mitochondria mass and overproduced ROS, suggesting the highly intimate correlation of β‐catenin with mitochondrial dysfunction.…”

TGF-β1 Signaling: Immune Dynamics of Chronic Kidney Diseases

“…In the canonical pathway, Smad2 and Smad3 are two key downstream mediators of TGF-β receptor that are highly activated in renal fibrosis ( 35 ). Subsequently, activated Smad2 and Smad3 first complexed with Smad4 ( 36 ), then translocated into the nucleus to transcriptionally regulate pro-fibrotic molecules expression, including collagens, fibronectin, and alpha-smooth muscle actin ( 37 – 39 ), thereby facilitating fibrotic responses. However, each Smads protein is functionally distinct in the pathogenesis of CKD.…”