A negative feedback loop between JNK-associated leucine zipper protein and TGF-β1 regulates kidney fibrosis

Qi, Yan; Zhu, Kai; Zhang, Lu; Fu, Qiang; Chen, Zhaowei; Liu, Shan; Fu, Dou; Nakazato, Ryota; Yoshioka, Katsuji; Diao, Bo; Ding, Guohua; Li, Yong; Wang, Huiming

doi:10.1038/s42003-020-1008-z

Cited by 12 publications

(5 citation statements)

References 83 publications

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“…Our previous studies identified a novel anti-fibrotic molecule of JLP that is exclusively expressed in renal tubular epithelial cells (TECs) in kidney tissue, with the potential to antagonize the TGF-β1-elicited effects of ECM production, EMT, autophagy activation, apoptosis, and cycle arrest in TECs in kidney fibrosis progression. Inhibition of autophagy by gaining expression of Jlp in TECs significantly retarded the fibrotic lesions both in vitro and in vivo [18]. Together with the similar findings of the protective role of Jlp in peritoneal fibrosis reported in this study, we concluded that permanent and overactivation of autophagy, a result partly due to JLP loss, might promote the development of peritoneal fibrosis.…”

Section: Discussionsupporting

confidence: 88%

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Loss of JNK-Associated Leucine Zipper Protein Promotes Peritoneal Dialysis-Related Peritoneal Fibrosis

et al. 2022

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Background: Peritoneal dialysis-related peritoneal fibrosis is the leading cause of peritoneal ultrafiltration failure. Multitude factors and pathological processes have been implicated in peritoneal fibrosis development and progression, whereas the intrinsic anti-fibrotic mechanism has rarely been explored. JNK-associated leucine zipper protein (JLP) has been recently found possessing powerful anti-fibrotic merits of overall antagonizing TGF-β-induced profibrotic effects. Objectives: We wondered whether JLP is expressed in the peritoneum, and if so, whether it exerts the anti-fibrotic effects similar to those in the kidney. Method: Here, we examined and confirmed JLP expression in peritoneum tissue of mice. Then, we established a peritoneal fibrosis model in Jlp wild-type and Jlp global deficient mice and observed the different effects of Jlp on peritoneal fibrosis progression. In vitro studies were performed on peritoneal mesothelial HMrSV5 cells with or without Jlp knockdown to investigate the underlying mechanism by which Jlp exerts anti-fibrotic effects. Results: We found that the expression of JLP decreased in a high-glucose peritoneal dialysis solution (HGPDS)-induced peritoneal fibrosis mouse model and in HGPDS-treated peritoneal mesothelial cell HMrSV5. JLP deletion exacerbated HGPDS-induced peritoneal fibrosis in peritoneal fibrosis mice, and knockdown of JLP resulted in an increased profibrotic response to HGPDS stimulation in HMrSV5 cells, which was associated with epithelial-to-mesenchymal transition, elevated autophagy, and apoptosis, as well as enhanced TGF-β1/Smad signaling activation. Conclusions: Our findings revealed a new anti-fibrotic factor of Jlp involved in peritoneal fibrosis induction and shed light on novel therapeutic targets in peritoneal ultrafiltration failure.

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Section: Discussionsupporting

confidence: 88%

“…Recently, it has also been found coordinating the cell process of autophagy [16]. Interestingly, our previous study demonstrated that JLP is involved in the regulation of TGF-β-induced renal fibrosis [17, 18], suggesting JLP as a potential anti-fibrosis factor. However, the role of JLP in peritoneal fibrosis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Loss of JNK-Associated Leucine Zipper Protein Promotes Peritoneal Dialysis-Related Peritoneal Fibrosis

et al. 2022

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“…Tubulo-interstitial fibrosis, a hallmark of CKD, is a progressive process, which is driven by activation of interstitial myofibroblasts and by an increase in pro-fibrotic and pro-inflammatory signals. Thus TGF-β1 signaling, reactivation of developmental pathways, and a decrease in the expression of protective factors, such as Klotho and bone morphogenetic protein 7 (BMP7) are found [8,[48][49][50][51][52][53][54][55]. Klotho is an anti-aging protein, which is predominantly expressed in the kidney, where it functions as a coreceptor for FGF23, regulating phosphate and calcium reabsorption and calcitriol metabolism [56].…”

Section: Introductionmentioning

confidence: 99%

Effect of NAD+ boosting on kidney ischemia-reperfusion injury

et al. 2021

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Acute kidney injury (AKI) is associated with a very high mortality and an increased risk for progression to chronic kidney disease (CKD). Ischemia-reperfusion injury (IRI) is a model for AKI, which results in tubular damage, dysfunction of the mitochondria and autophagy, and in decreased cellular nicotinamide adenine dinucleotide (NAD+) with progressing fibrosis resulting in CKD. NAD+ is a co-enzyme for several proteins, including the NAD+ dependent sirtuins. NAD+ augmentation, e.g. by use of its precursor nicotinamide riboside (NR), improves mitochondrial homeostasis and organismal metabolism in many species. In the present investigation the effects of prophylactic administration of NR on IRI-induced AKI were studied in the rat. Bilateral IRI reduced kidney tissue NAD+, caused tubular damage, reduced α-Klotho (klotho), and altered autophagy flux. AKI initiated progression to CKD, as shown by induced profibrotic Periostin (postn) and Inhibin subunit beta-A, (activin A / Inhba), both 24 hours and 14 days after surgery. NR restored tissue NAD+ to that of the sham group, increased autophagy (reduced p62) and sirtuin1 (Sirt1) but did not ameliorate renal tubular damage and profibrotic genes in the 24 hours and 14 days IRI models. AKI induced NAD+ depletion and impaired autophagy, while augmentation of NAD+ by NR restored tissue NAD+ and increased autophagy, possibly serving as a protective response. However, prophylactic administration of NR did not ameliorate tubular damage of the IRI rats nor rescued the initiation of fibrosis in the long-term AKI to CKD model, which is a pivotal event in CKD pathogenesis.

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“…Paraffin-embedded sections with 4 μm thickness from each isolated kidney were stained with hematoxylin and eosin or Sirius red following the standard procedure, respectively. The tubular damage and tubulointerstitial fibrosis were measured as described [21] .…”

Section: Methodsmentioning

confidence: 99%

Identification of Hub Genes Correlated with the Initiation and Development in Chronic Kidney Disease via Bioinformatics Analysis

Zhu

Gao

et al. 2023

Kidney Blood Press Res

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Introduction: Chronic kidney disease (CKD) is a major public health issue worldwide, which is characterized by irreversible loss of nephron and renal function. However, the molecular mechanism of CKD remains underexplored. Methods: This study integrated three transcriptional profile datasets to investigate the molecular mechanism of CKD. The differentially expressed genes (DEGs) between Con and unilateral ureteral obstruction (UUO)-operated mice were analyzed by utilizing the limma package in R. The shared DEGs were analyzed by Gene Ontology (GO) and functional enrichment. Protein-protein interactions (PPI) were constructed by utilizing the STRING database. Hub genes were analyzed by MCODE and Cytohubba. We further validated the gene expression by using the other dataset and mice UUO model. Results: A total of 315 shared DEGs between Con and UUO samples were identified. Gene function and KEGG pathway enrichment revealed that DEGs were mainly enriched in inflammatory response, immune system process and chemokine signaling pathway. Two modules were clustered based on PPI network analysis. Module 1 contained 13 genes, related to macrophage activation, migration, and chemotaxis. Ten hub genes were identified by PPI network analysis. Subsequently, the expression levels of hub genes were validated with the other dataset. Finally, these four validated hub genes were further confirmed by our UUO mice. Three validated hub genes, Gng2, Pf4 and Ccl9, showed significant response to UUO. Conclusion: Our study reveals the coordination of genes during UUO, and provides a promising gene panel CKD treatment. GNG2 and PF4 were identified as potential targets for developing CKD drugs.

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A negative feedback loop between JNK-associated leucine zipper protein and TGF-β1 regulates kidney fibrosis

Cited by 12 publications

References 83 publications

Loss of JNK-Associated Leucine Zipper Protein Promotes Peritoneal Dialysis-Related Peritoneal Fibrosis

Loss of JNK-Associated Leucine Zipper Protein Promotes Peritoneal Dialysis-Related Peritoneal Fibrosis

Effect of NAD+ boosting on kidney ischemia-reperfusion injury

Identification of Hub Genes Correlated with the Initiation and Development in Chronic Kidney Disease via Bioinformatics Analysis

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