Snail and kidney fibrosis

Simon-Tillaux, Noémie; Hertig, Alexandre

doi:10.1093/ndt/gfw333

Cited by 35 publications

(34 citation statements)

References 100 publications

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“…As shown in Figure e–g, the protein expression levels of the active and total form of β‐catenin were significantly upregulated following the development of aging. We then inspected PAI‐1, Snail1, and MMP‐7, the three important targets that reflect the activity of Wnt/β‐catenin signaling (He et al, , ; Simon‐Tillaux & Hertig, ). As shown in Figure e,h,i, the expression levels of PAI‐1 and Snail1 were significantly induced in aging mice, especially in 24‐month‐old mice.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…We also examined potential inflammatory signals expressed by the collecting duct on the basis of existing evidence. 40 We looked at the differential expression of KLF5, P2ry14, and Snail 40,41,55,56 and found no significant difference between SKO and DKO kidneys (Supplemental Figure 10, A-C). It is likely that signals other than the ones evaluated above underlie the chronic kidney injury phenotype observed in the DKO mice.…”

Section: Ckd Occurs Due To Loss Of Xbp1s Homeostatic Activity In the mentioning

confidence: 99%

Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts

Ishikawa¹,

Fedeles²,

Marlier³

et al. 2019

JASN

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Background SEC63 encodes a resident protein in the endoplasmic reticulum membrane that, when mutated, causes human autosomal dominant polycystic liver disease. Selective inactivation of Sec63 in all distal nephron segments in embryonic mouse kidney results in polycystin-1-mediated polycystic kidney disease (PKD). It also activates the Ire1a-Xbp1 branch of the unfolded protein response, producing Xbp1s, the active transcription factor promoting expression of specific genes to alleviate endoplasmic reticulum stress. Simultaneous inactivation of Xbp1 and Sec63 worsens PKD in this model. MethodsWe explored the renal effects of postnatal inactivation of Sec63 alone or with concomitant inactivation of Xbp1 or Ire1a, specifically in the collecting ducts of neonatal mice. ResultsThe later onset of inactivation of Sec63 restricted to the collecting duct does not result in overt activation of the Ire1a-Xbp1 pathway or cause polycystin-1-dependent PKD. Inactivating Sec63 along with either Xbp1 or Ire1a in this model causes interstitial inflammation and associated fibrosis with decline in kidney function over several months. Re-expression of XBP1s in vivo completely rescues the chronic kidney injury observed after inactivation of Sec63 with either Xbp1 or Ire1a. ConclusionsIn the absence of Sec63, basal levels of Xbp1s activity in collecting ducts is both necessary and sufficient to maintain proteostasis (protein homeostasis) and protect against inflammation, myofibroblast activation, and kidney functional decline. The Sec63-Xbp1 double knockout mouse offers a novel genetic model of chronic tubulointerstitial kidney injury, using collecting duct proteostasis defects as a platform for discovery of signals that may underlie CKD of disparate etiologies.

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“…The expression of Snail correlated with tumor grade, metastasis and could be used as a prognostic marker for poor outcome in patients with head and neck squamous cell carcinoma . In addition, several studies have shown that Snail was related to various fibrosis . As such, targeting Snail may be a promising therapeutic approach to attenuate the progression of precancerous OSF.…”

Section: Introductionmentioning

confidence: 99%

Hinokitiol ablates myofibroblast activation in precancerous oral submucous fibrosis by targeting Snail

Yang

Chiu

et al. 2018

Environmental Toxicology

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Oral submucous fibrosis (OSF) is a precancerous condition with symptoms of limited mouth opening and areca nut chewing habit has been implicated in its pathogenesis. Hinokitiol, a natural tropolone derived from Chamacyparis taiwanensis, has been reported to improve oral lichen planus and inhibit various cancer cells. Here, we showed that hinokitiol reduced the myofibroblast activities in fBMFs and prevented the arecoline-induced transdifferentiation. Treatment of hinokitiol dose-dependently downregulated the myofibroblast markers as well as various EMT transcriptional factors. In particular, we identified that Snail was able to bind to the E-box in the α-SMA promoter. Our data suggested that exposure of fBMFs to hinokitiol mitigated the hallmarks of myofibroblasts, while overexpression of Snail eliminated the effect of hinokitiol. These findings revealed that the inhibitory effect of hinokitiol on myofibroblasts was mediated by repression of α-SMA via regulation of Snail and showed the anti-fibrotic potential of hinokitiol in the treatment of OSF.

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Snail and kidney fibrosis

Cited by 35 publications

References 100 publications

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

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

Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts

Hinokitiol ablates myofibroblast activation in precancerous oral submucous fibrosis by targeting Snail

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