CXCR4 induces podocyte injury and proteinuria by activating β-catenin signaling

Mo, Hongyan; Ren, Qian; Duan, Song; Xu, Bo; Zhou, Dong; Xue, Hong; Hou, Fan Fan; Zhou, Lili; Liu, Youhua

doi:10.7150/thno.65948

Cited by 22 publications

(12 citation statements)

References 49 publications

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“…This cascade of phosphorylation of signalling proteins is also consistent with our previous findings in other classic CKD models. 21,22 Meanwhile, CXCR4 triggered renal tubular cell senescence, renal fibrotic lesions and FAO deficiency (Figures 2, 5 and 6). Knockdown of CXCR4 in ADR mice model ameliorated renal injuries, and inhibited β-catenin (Figure 3), preserved mitochondrial function and retarded cellular senescence (Figure 4).…”

Section: Discussionmentioning

confidence: 97%

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C‐X‐C chemokine receptor type 4 promotes tubular cell senescence and renal fibrosis through β‐catenin‐inhibited fatty acid oxidation

Wu,

Chen,

et al. 2024

J Cellular Molecular Medi

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The prevalence of chronic kidney disease (CKD) is highly increasing. Renal fibrosis is a common pathological feature in various CKD. Previous studies showed tubular cell senescence is highly involved in the pathogenesis of renal fibrosis. However, the inducers of tubular senescence and the underlying mechanisms have not been fully investigated. C‐X‐C motif chemokine receptor 4 (CXCR4), a G‐protein‐coupled seven‐span transmembrane receptor, increases renal fibrosis and plays an important role in tubular cell injury. Whereas, whether CXCR4 could induce tubular cell senescence and the detailed mechanisms have not studied yet. In this study, we adopted adriamycin nephropathy and 5/6 nephrectomy models, and cultured tubular cell line. Overexpression or knockdown of CXCR4 was obtained by injection of related plasmids. We identified CXCR4 increased in injury tubular cells. CXCR4 was expressed predominantly in renal tubular epithelial cells and co‐localized with adipose differentiation‐related protein (ADRP) as well as the senescence‐related protein P16INK4A. Furthermore, we found overexpression of CXCR4 greatly induced the activation of β‐catenin, while knockdown of CXCR4 inhibited it. We also found that CXCR4 inhibited fatty acid oxidation and triggered lipid deposition in tubular cells. To inhibit β‐catenin by ICG‐001, an inhibitor of β‐catenin, could significantly block CXCR4‐suppressed fatty acid oxidation. Taken together, our results indicate that CXCR4 is a key mediator in tubular cell senescence and renal fibrosis. CXCR4 promotes tubular cell senescence and renal fibrosis by inducing β‐catenin and inhibiting fatty acid metabolism. Our findings provide a new theory for tubular cell injury in renal fibrosis.

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Section: Discussionmentioning

confidence: 97%

“…[17][18][19][20] Our previous studies also found that CXCR4 promotes tubular cell injury and renal fibrosis via activating β-catenin signalling. [21][22][23] Wnt/β-catenin signalling is an evolutionarily conserved pathway.…”

Section: Introductionmentioning

confidence: 99%

C‐X‐C chemokine receptor type 4 promotes tubular cell senescence and renal fibrosis through β‐catenin‐inhibited fatty acid oxidation

Wu,

Chen,

et al. 2024

J Cellular Molecular Medi

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“…Paraffin-embedded mouse and human kidney sections (3 μm thickness) were prepared by a routine procedure (48,49). The sections were stained with Sirius red staining or Masson's trichrome staining, according to the manufacturer's protocols, respectively.…”

Section: Histology Immunohistochemical and Immunofluorescence Stainingmentioning

confidence: 99%

Insulin-like growth factor 2 mRNA-binding protein 3 promotes kidney injury by regulating β-catenin signaling

Duan¹,

Shang²,

Long³

et al. 2023

JCI Insight

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Wnt/β-catenin is a developmental signaling that plays a crucial role in driving kidney fibrosis after injury. Activation of β-catenin is presumed to be regulated through the post-translational protein modification. Little is known about whether β-catenin is also subjected to regulation at the posttranscriptional mRNA level. Here, we report that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays a pivotal role in regulating β-catenin. IGF2BP3 was upregulated in renal tubular epithelium of various animal models and patients with chronic kidney disease. IGF2BP3 not only was a direct downstream target of Wnt/β-catenin but also obligatory for transducing Wnt signal. In vitro, overexpression of IGF2BP3 in kidney tubular cells induced fibrotic responses, whereas knockdown of endogenous IGF2BP3 prevented the expression of injury and fibrosis markers in tubular cells after Wnt3a stimulation. In vivo, exogenous IGF2BP3 promoted β-catenin activation and aggravated kidney fibrosis, while knockdown of IGF2BP3 ameliorated renal fibrotic lesions after obstructive injury. RNA immunoprecipitation and mRNA stability assay revealed that IGF2BP3 directly bound to β-catenin mRNA and stabilized it from degradation. Furthermore, knockdown of IGF2BP3 in tubular cells accelerated β-catenin mRNA degradation in vitro. These studies demonstrate that IGF2BP3 promotes β-catenin signaling and drives kidney fibrosis, which may be mediated through stabilizing β-catenin mRNA. Our findings uncover a new dimension of the complex regulation of Wnt/β-catenin signaling and suggest a potential target for therapeutic intervention of fibrotic kidney diseases.

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“…Formalin-xed Para n-embedded mouse kidney sections (4 µm) were prepared, dewaxed, washed in down-graded alcohols and water by a routine procedure. Hematoxylin-eosin (HE) staining and Masson's trichrome staining (MTS) were performed using routine protocol (21). For immunohistochemical staining, depara nized sections were incubated with 3% H2O2 solution to inhibit endogenous peroxidase activity.…”

Section: Histology and Immunohistochemical Stainingmentioning

confidence: 99%

Kidney tubular epithelial cells control interstitial fibroblast fate by releasing TNFAIP8-encapsulated exosomes

Liu

Miao

et al. 2023

Preprint

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Kidney fibrosis, characterized by the activation and expansion of the matrix-producing fibroblasts, is the common outcome of chronic kidney disease (CKD). While fibroblast proliferation is well studied in CKD, little is known about the regulation and mechanism of fibroblast depletion. Here, we show that exosomes derived from stressed/injured tubules play a pivotal role in dictating fibroblast apoptosis and fate. When human kidney tubular cells (HK-2) were stimulated with TGF-β1, they produced and released increased amounts of exosomes (TGFβ-Exo), which prevented renal interstitial fibroblasts from apoptosis. In vivo, injections of TGFβ-Exo promoted renal fibroblast survival, whereas blockade of exosome secretion accelerated fibroblast apoptosis in obstructive nephropathy. Proteomics profiling identified the tumor necrosis factor-α-induced protein 8 (TNFAIP8) as a key component enriched in TGFβ-Exo. TNFAIP8 was induced in renal tubular epithelium and enriched in the exosomes from fibrotic kidneys. Knockdown of TNFAIP8 in tubular cells abolished the ability of TGFβ-Exo to prevent fibroblast apoptosis. In vivo, gain- or loss- of TNFAIP8 prevented or aggravated renal fibroblast apoptosis after obstructive injury. Mechanistically, exosomal-TNFAIP8 promoted p53 ubiquitination leading to its degradation, thereby inhibiting fibroblasts apoptosis and inducing their proliferation. Collectively, these results indicate that tubule-derived exosomes play a critical role in controlling the size of fibroblast population during renal fibrogenesis through shuttling TNFAIP8 to block p53 signaling. Strategies to target exosomes may be effective strategies for the therapy of fibrotic CKD.

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CXCR4 induces podocyte injury and proteinuria by activating β-catenin signaling

Cited by 22 publications

References 49 publications

C‐X‐C chemokine receptor type 4 promotes tubular cell senescence and renal fibrosis through β‐catenin‐inhibited fatty acid oxidation

C‐X‐C chemokine receptor type 4 promotes tubular cell senescence and renal fibrosis through β‐catenin‐inhibited fatty acid oxidation

Insulin-like growth factor 2 mRNA-binding protein 3 promotes kidney injury by regulating β-catenin signaling

Kidney tubular epithelial cells control interstitial fibroblast fate by releasing TNFAIP8-encapsulated exosomes

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