Antagonism of Canonical Wnt/β-Catenin Signaling

Floege, Jürgen

doi:10.1681/asn.2014060567

Cited by 11 publications

(10 citation statements)

References 16 publications

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“…This goes along with an increased expression of DKK-1 and sclerostin, as recently observed in the tubular epithelium of mice subjected to renal injury mimicking stage 2 CKD [43]. In addition, Bstandard^nephrological therapeutics such as vitamin D [42] and ACE-inhibition [44] interfere with the Wnt signaling cascade.…”

mentioning

confidence: 54%

From skeletal to cardiovascular disease in 12 steps—the evolution of sclerostin as a major player in CKD-MBD

et al. 2015

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Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology.

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confidence: 54%

From skeletal to cardiovascular disease in 12 steps—the evolution of sclerostin as a major player in CKD-MBD

et al. 2015

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“…Inhibition of Wnt/β‐catenin could simultaneously block multiple RAS genes. This certainly provides a more effective RAS blockade against aldosterone breakthrough as compared with inhibition by an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) (Floege, ). It is noteworthy that angiotensin II blockade provides anti‐aging benefits (de Cavanagh, Inserra, & Ferder, ); hence, a more powerful RAS blockade would be of great importance.…”

Section: Discussionmentioning

confidence: 99%

Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction

et al. 2019

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Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age‐related renal fibrosis are not elucidated. Herein, we found that Wnt/β‐catenin signaling and renin–angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β‐catenin activity, abolished renal fibrosis in d‐galactose (d‐gal)‐induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria‐targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC‐8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d‐gal triggered the transduction of Wnt/β‐catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC‐8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β‐catenin signaling and the RAS could slow the onset of age‐related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction.

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“…15,20,21,23 The importance of sustained Wnt signaling in driving AKI to CKD progression is also substantiated by in vivo expression of Wnt1, the prototype of Wnt ligands that is highly induced after IRI (Figures 2 and 3), or inhibiting Wnt/b-catenin signaling by using a small molecule inhibitor ICG-001. 34,43,44 Notably, we selected to manipulate Wnt/b-catenin at 5 days after IRI (Figures 4 and 7), a time point that extends beyond the initial injury and early repair/ regeneration phases after AKI, to assess the potential role of Wnt signaling in modulating AKI to CKD progression. These data clearly suggest that a sustained activation of Wnt/b-catenin beyond the injury and repair phases after AKI would result in maladaptive responses characterized by persistent fibroblast activation, excessive matrix accumulation, and renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression

Lin

Zhou²,

Tan

et al. 2015

JASN

207

214

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AKI is increasingly recognized as a major risk factor for progression to CKD. However, the factors governing AKI to CKD progression are poorly understood. In this study, we investigated this issue using moderate (20 minutes) and severe (30 minutes) ischemia/reperfusion injury (IRI) in mice. Moderate IRI led to acute kidney failure and transient Wnt/b-catenin activation, which was followed by the restoration of kidney morphology and function. However, severe IRI resulted in sustained and exaggerated Wnt/ b-catenin activation, which was accompanied by development of renal fibrotic lesions characterized by interstitial myofibroblast activation and excessive extracellular matrix deposition. To assess the role of sustained Wnt/b-catenin signaling in mediating AKI to CKD progression, we manipulated this signaling by overexpression of Wnt ligand or pharmacologic inhibition of b-catenin. In vivo, overexpression of Wnt1 at 5 days after IRI induced b-catenin activation and accelerated AKI to CKD progression. Conversely, blockade of Wnt/b-catenin by small molecule inhibitor ICG-001 at this point hindered AKI to CKD progression. In vitro, Wnt ligands induced renal interstitial fibroblast activation and promoted fibronectin expression. However, activated fibroblasts readily reverted to a quiescent phenotype after Wnt ligands were removed, suggesting that fibroblast activation requires persistent Wnt signaling. These results indicate that sustained, but not transient, activation of Wnt/b-catenin signaling has a decisive role in driving AKI to CKD progression. 27: 172727: -174027: , 201627: . doi: 10.1681 AKI is responsible for about 2 million deaths each year worldwide, and its incidence is rising. 1-3 AKI is increasingly common in critically ill patients, and those patients with severe AKI requiring dialysis have a mortality rate of .50%. In contrast to the traditional belief that survivors of AKI tend to fully recover renal function, there is growing evidence that patients who survive an episode of AKI will have a significant risk of developing progressive CKD and even ESRD. 1,2,4 Evidence is also mounting that the severity and frequency of AKI seem to be closely correlated with poor patient long-term outcome, 5,6 suggesting that AKI may be a predictive and causative factor for subsequent development of CKD. In this context, delineation of the underlying mechanisms governing the different courses of long-term outcome after AKI will not only shed new light on understanding the pathophysiology of AKI-CKD progression but also is instrumental in designing rational strategies for therapeutic intervention. J Am Soc NephrolWnt/b-catenin is a developmental signaling pathway that plays an essential role in regulating

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Antagonism of Canonical Wnt/β-Catenin Signaling

Cited by 11 publications

References 16 publications

From skeletal to cardiovascular disease in 12 steps—the evolution of sclerostin as a major player in CKD-MBD

From skeletal to cardiovascular disease in 12 steps—the evolution of sclerostin as a major player in CKD-MBD

Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction

Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression

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