Wnt/β-catenin signaling in kidney injury and repair: a double-edged sword

Zhou, Dong; Tan, Roderick J.; Fu, Haiyan; Liu, Youhua

doi:10.1038/labinvest.2015.153

Cited by 161 publications

(144 citation statements)

References 126 publications

(164 reference statements)

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“…A variety of nephrotoxic events lead to marked accumulation of β-catenin in renal tubules [20,21]. In both folic acid nephropathy and ischemia-reperfusion, tubule-specific ablation of β-catenin is harmful, leading to increased mortality, renal injury, and tubular cell apoptosis [18].…”

Section: Epithelial-mesenchymal Communicationmentioning

confidence: 99%

Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury

2016

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Background: A wide variety of kidney diseases ultimately lead to tubulointerstitial damage. The initial site of injury is usually the renal tubules, with activation of fibroblasts occurring later. Self-limited disease is characterized by transient cellular activation with timed deactivation and ultimately a return to normal functioning, whereas sustained responses characterize chronic disease and the development of irreversible fibrosis. The underlying molecular and cellular mechanisms of this cascade of events remain an area of active research. Current data overwhelmingly support a role for crosstalk between the tubular epithelium and the interstitial fibroblast that mediates both repair/regeneration and progressive disease. This epithelial-mesenchymal communication (EMC) is regulated by a variety of soluble ligands binding to cell surface receptors to induce intracellular signaling events. Summary: EMC is an important mechanism whereby tubular epithelium and fibroblasts/mesenchymal cells crosstalk to affect renal physiology and pathology. Numerous soluble factors such as sonic hedgehog, Wnt ligands, transforming growth factor-β, hepatocyte growth factor, connective tissue growth factor, and angiotensin II all participate in bidirectional EMC. Recent studies have also identified exosomes as a vehicle to mediate EMC during kidney injury. In general, while the short-term activity of EMC factors is renoprotective, prolonged activation of these factors leads to chronic disease and fibrosis. Key Messages: The discovery of a complex and intricate system of communication between tubular cells and fibroblasts is a new paradigm in our understanding of renal fibrosis. An appreciation of both their regenerative and pathologic functions will inform the development and use of targeted therapeutic interventions.

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Section: Epithelial-mesenchymal Communicationmentioning

confidence: 99%

Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury

2016

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“…For instance, besides Shh signaling pathway, TGF-β1, Wnt/β-catenin and Notch pathways are well recognized to play crucial roles in the evolution of renal fibrosis in CKD (Bielesz et al, 2010; He and Dai, 2015; He et al, 2009; Tan et al, 2014; Zhou et al, 2016). However, the role of Shh signaling is quite unique in this process in that it specifically targets interstitial cells, while it is mainly produced by the injured tubules.…”

Section: Targets and Mechanism Of Shh Signaling In Kidney Fibrosismentioning

confidence: 99%

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

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The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog (Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease (CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelial-mesenchymal communication (EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

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“…Given the significant role of β-catenin in kidney development and repair after AKI [15, 20], we evaluated the expression of β-catenin in tubular cells after CM treatment. In the cisplatin group, the protein expression of β-catenin was significantly lower than that in the control group.…”

Section: Resultsmentioning

confidence: 99%

“…Wnt signaling, one of the evolutionarily conserved pathways, is associated with organ development, homeostasis and tissue repair [13-15]. When wnt ligands bind to Frizzled receptors and LRP5/6 coreceptors, the β-catenin degradation complex is sequestered, leading to the translocation of β-catenin to the nucleus to prompt the expression of target genes regulating cell fate, proliferation and apoptosis [16-19].…”

Section: Introductionmentioning

confidence: 99%

Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

Jiao

Cai²,

Yu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cisplatin-induced acute kidney injury (AKI) involves damage to tubular cells via excess reactive oxygen species (ROS) generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived conditioned medium (CM) against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data showed that the tubular β-catenin level was lower in AKI patients experiencing partial recovery than in patients experiencing complete recovery. Conclusion: The activation of the wnt/β-catenin pathway by CM protects against cisplatin-induced kidney injury, resulting in reduced apoptosis and intracellular ROS levels.

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Wnt/β-catenin signaling in kidney injury and repair: a double-edged sword

Cited by 161 publications

References 126 publications

Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury

Signaling Crosstalk between Tubular Epithelial Cells and Interstitial Fibroblasts after Kidney Injury

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

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