Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis

Xu, Guibin; Fei, Yue; Huang, Hai; He, Yongzhong; Li, Xun; Zhao, Haibo; Su, Zhengming; Jiang, Xianhan; Li, Wenjiao; Zou, Jing; Chen, Qi; Liu, Leyuan

doi:10.18632/aging.100957

Cited by 22 publications

(25 citation statements)

References 36 publications

(49 reference statements)

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“…As indicated by the systems pharmacology prediction, a large number of candidate targets of NDQ were related to the TGF-β and p38 MAPK signaling pathways, which are closely related to renal fibrosis [ 42 – 45 ]. By using enzyme-linked immunosorbent assays (ELISA), we first evaluated some classical renal fibrosis-related factors such as type III procollagen peptide (PCIII) [ 46 ], type IV collagen (COLIV) [ 47 ], laminin (LN) [ 48 ], and fibronectin (FN) [ 49 ] in 5/6 nephrectomy rats. As shown in Figures 7A-7D , NDQ treatment decreased the serum levels of PCIII, COLIV, LN, and FN.…”

Section: Resultsmentioning

confidence: 99%

NiaoDuQing granules relieve chronic kidney disease symptoms by decreasing renal fibrosis and anemia

Wang

Jia

et al. 2017

Oncotarget

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NiaoDuQing (NDQ) granules, a traditional Chinese medicine, has been clinically used in China for over fourteen years to treat chronic kidney disease (CKD). To elucidate the mechanisms underlying the therapeutic benefits of NDQ, we designed an approach incorporating chemoinformatics, bioinformatics, network biology methods, and cellular and molecular biology experiments. A total of 182 active compounds were identified in NDQ granules, and 397 putative targets associated with different diseases were derived through ADME modelling and target prediction tools. Protein-protein interaction networks of CKD-related and putative NDQ targets were constructed, and 219 candidate targets were identified based on topological features. Pathway enrichment analysis showed that the candidate targets were mostly related to the TGF-β, the p38MAPK, and the erythropoietin (EPO) receptor signaling pathways, which are known contributors to renal fibrosis and/or renal anemia. A rat model of CKD was established to validate the drug-target mechanisms predicted by the systems pharmacology analysis. Experimental results confirmed that NDQ granules exerted therapeutic effects on CKD and its comorbidities, including renal anemia, mainly by modulating the TGF-β and EPO signaling pathways. Thus, the pharmacological actions of NDQ on CKD symptoms correlated well with in silico predictions.

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“…Inhibition of the autophagy-related protein MAP1S (microtubule associated protein 1S), which interacts with LC3 and positively regulates autophagosome biogenesis, reduces FN1 degradation in HCC cells [150]. Loss of MAP1S decreases FN1 degradation, resulting in increased FN1 protein levels, organ fibrosis, and HCC tumorigenesis in vivo [149,151,152]. Similarly, increased FN1 levels are correlated with decreased MAP1S expression in patient samples of renal fibrosis [152].…”

Section: Reciprocal Regulation Between Autophagy and The Ecmmentioning

confidence: 99%

“…Loss of MAP1S decreases FN1 degradation, resulting in increased FN1 protein levels, organ fibrosis, and HCC tumorigenesis in vivo [149,151,152]. Similarly, increased FN1 levels are correlated with decreased MAP1S expression in patient samples of renal fibrosis [152]. Although MAP1S promotes FN1 turnover, the role of autophagy in this process is not defined.…”

Section: Reciprocal Regulation Between Autophagy and The Ecmmentioning

confidence: 99%

Mechanisms and context underlying the role of autophagy in cancer metastasis

et al. 2018

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Macroautophagy/autophagy is a fundamental cellular degradation mechanism that maintains cell homeostasis, regulates cell signaling, and promotes cell survival. Its role in promoting tumor cell survival in stress conditions is well characterized, and makes autophagy an attractive target for cancer therapy. Emerging research indicates that autophagy also influences cancer metastasis, which is the primary cause of cancer-associated mortality. However, data demonstrate that the regulatory role of autophagy in metastasis is multifaceted, and includes both metastasis-suppressing and -promoting functions. The metastasis-suppressing functions of autophagy, in particular, have important implications for autophagy-based treatments, as inhibition of autophagy may increase the risk of metastasis. In this review, we discuss the mechanisms and context underlying the role of autophagy in metastasis, which include autophagy-mediated regulation of focal adhesion dynamics, integrin signaling and trafficking, Rho GTPase-mediated cytoskeleton remodeling, anoikis resistance, extracellular matrix remodeling, epithelial-to-mesenchymal transition signaling, and tumor-stromal cell interactions. Through this, we aim to clarify the context-dependent nature of autophagy-mediated metastasis and provide direction for further research investigating the role of autophagy in cancer metastasis.

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“…Autophagy directly regulates pyroptosis [ 22 – 24 ]. Reducing the expression of PRDX3 in BPH-1 cells led to an increase in the levels of caspase 1 (P45) and a reduction in the levels of Caspase 1 (P20) (Figure 5A–5C ), suggesting an impairment of caspase 1 activation.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrion-associated protein peroxiredoxin 3 promotes benign prostatic hyperplasia through autophagy suppression and pyroptosis activation

Jiang

Han

et al. 2017

Oncotarget

Self Cite

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Benign prostatic hyperplasia (BPH) is one of the most common diseases in the senior men and age plays an important role in the initiation and development of BPH. Mammalian cells primarily use the autophagy-lysosome system to degrade misfolded/aggregated proteins and dysfunctional organelles such as mitochondria and suppress pyroptosis, a type of cell death that stimulates inflammatory responses and growth of other cells around. Peroxiredoxin 3 (PRDX3) is the only mitochondrion-associated member of peroxiredoxin family enzymes that exert their protective antioxidant role in cells through their peroxidase activity. We hypothesized that PRDX3 may inhibit autophagy to activate pyroptosis to induce growth of prostatic epithelial cells. Here we show that PRDX3 maintained the integrity of mitochondria and its depletion led to an enhancement of oxidative stresses. PRDX3-associated and PRDX3-free mitochondria co-existed in the same cells. PRDX3 expressed at higher levels in prostatic epithelial cells in prostate tissues from BPH patients and BPH-representative cell line than in prostate tissues from healthy donors and a cell line representing normal epithelial cells. PRDX3 suppressed autophagy flux and activated pyroptosis to induce inflammatory responses and stimulate the over-growth of prostate tissues. Therefore, higher levels of PDRX3 in prostatic epithelial cells may promote the initiation and development of BPH through autophagy inhibition and pyroptosis activation.

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“…The persistent and active autophagy of renal tubules aggravated renal interstitial fibrosis. The profibrotic function of autophagy is based on the regulation on tubular cells death, interstitial inflammation, and the production of profibrotic factors [ 24 ], whereas the lack of autophagy-related factors could cause the accumulation of FN and the development of renal fibrosis [ 25 ]. We found that SIN-HCl not only attenuates renal fibrosis but also attenuates excessive autophagy in renal injury caused by adriamycin; basal autophagy was also upregulated by SIN-HCl.…”

Section: Discussionmentioning

confidence: 99%

Sinomenine Hydrochloride Attenuates Renal Fibrosis by Inhibiting Excessive Autophagy Induced by Adriamycin: An Experimental Study

Zhao

Yang

Qiu

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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The objective of this study is to investigate if sinomenine hydrochloride (SIN-HCl) could be effective against adriamycin-induced renal fibrosis by regulating autophagy in a rat model. Forty male Sprague-Dawley (SD) rats were randomly divided into control group, model group, telmisartan group, and SIN-HCl group; rat model was induced by adriamycin; all rats were given intragastric administration for 6 weeks. Urine was collected from rats in metabolic cages to determine 24 h protein level. This was done after intragastric administration for the first two weeks and then once for every two weeks. Renal pathological changes were examined by the staining of HE, Masson, and PASM. Expressions and distributions of fibronectin (FN), laminin (LN), light chain 3 (LC3), and Beclin-1 were observed by immunohistochemistry. SIN-HCl ameliorates proteinuria, meanwhile attenuating the renal pathological changes in adriamycin-induced rats and also attenuating renal fibrosis and excessive autophagy by reducing the expression of FN, LN, LC3, and Beclin-1. SIN-HCl attenuates renal fibrosis by inhibiting excessive autophagy induced by adriamycin and upregulates the basal autophagy.

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Defects in MAP1S-mediated autophagy turnover of fibronectin cause renal fibrosis

Cited by 22 publications

References 36 publications

NiaoDuQing granules relieve chronic kidney disease symptoms by decreasing renal fibrosis and anemia

Mechanisms and context underlying the role of autophagy in cancer metastasis

Mitochondrion-associated protein peroxiredoxin 3 promotes benign prostatic hyperplasia through autophagy suppression and pyroptosis activation

Sinomenine Hydrochloride Attenuates Renal Fibrosis by Inhibiting Excessive Autophagy Induced by Adriamycin: An Experimental Study

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