Nrf2 signaling attenuates epithelial-to-mesenchymal transition and renal interstitial fibrosis via PI3K/Akt signaling pathways

Wang, Jun; Zhu, Haobo; Huang, Lingli; Zhu, Xiaofang; Sha, Jintong; Li, Guogen; Ma, Geng; Zhang, Wei; Gu, Min; Guo, Yunfei

doi:10.1016/j.yexmp.2019.104296

Cited by 45 publications

(31 citation statements)

References 41 publications

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“…A total of 40 signaling pathways were identified. In the most significantly altered signaling pathway in this study, fibrosis was reported in previous studies to be involved in the ‘Hedgehog signaling pathway’ ( 35 – 37 ), ‘ABC transporters’ ( 38 ), ‘ErbB signaling pathway’ ( 39 , 40 ), ‘cAMP signaling pathway’ ( 41 , 42 ), ‘Relaxin signaling pathway’ ( 43 , 44 ), ‘Ras signaling pathway’ ( 45 , 46 ) and ‘PI3K-Akt signaling pathway’ ( 47 , 48 ). Additionally, six ECM-associated pathways were directly associated with renal fibrosis.…”

Section: Discussionsupporting

confidence: 57%

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Zhu

Wang

et al. 2020

Mol Med Rep

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in acute aristolochic acid nephropathy (aan), aristolochic acid (aa) induces renal injury and tubulointerstitial fibrosis. However, the roles of micrornas (mirnas/mirs) and mrnas involved in aan are not clearly understood. The aim of the present study was to examine aa-induced genome-wide differentially expressed (de) mirnas and de mrnas using deep sequencing in mouse kidneys, and to analyze their regulatory networks. in the present self-controlled study, mice were treated with 5 mg/kg/day aa for 5 days, following unilateral nephrectomy. AA-induced renal injury and tubulointerstitial fibrosis were detected using hematoxylin and eosin staining and Masson's trichrome staining in the mouse kidneys. a total of 82 DE miRNAs and 4,605 DE mRNAs were identified between the aa-treated group and the self-control group. of these de mirnas and mrnas, some were validated using reverse transcription-quantitative Pcr. expression levels of the profibrotic miR-21, miR-433 and miR-132 families were significantly increased, whereas expression levels of the anti-fibrotic miR-122-5p and let-7a-1-3p were significantly decreased. Functions and signaling pathways associated with the de mirnas and mrnas were analyzed using Gene ontology and Kyoto encyclopedia of Genes and Genomes (KeGG). a total of 767 de pairs (in opposing directions) of mirnas and their mrna targets were identified. among these, regulatory networks of mirnas and mrnas were analyzed using KeGG to identify enriched signaling pathways and extracellular matrix-associated pathways. in conclusion, the present study identified genome-wide de mirnas and mrnas in the kidneys of aa-treated mice, as well as their regulatory pairs and signaling networks. The present results may improve the understanding of the role of de mirnas and their mrna targets in the pathophysiology of acute aan.

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Section: Discussionsupporting

confidence: 57%

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Zhu

Wang

et al. 2020

Mol Med Rep

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“…According to the above results, we became interested in investigating the underlying molecular mechanism of Cx43-mediated repression of EMT and reversion of TAM resistance in breast cancer cells. It has been proven that PI3K/Akt pathway plays a vital role in activating EMT and drug resistance in malignancies 33 , 34 . There are reports showing that Cx43 could activate PI3K/Akt signaling and PI3K/Akt signaling could increase Cx43 phosphorylation in cardiomyocytes 35 , 36 .…”

Section: Resultsmentioning

confidence: 99%

Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway

Wu¹,

Zhou²,

Hou³

et al. 2021

Int. J. Biol. Sci.

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Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.

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“…The authors suggested that the nephroprotective effect of allicin was dependent on the TGF-β1/ERK 1/2 pathway [26]. Likewise, it is known that Nrf2 is capable of conferring antifibrotic effects mediated by the inactivation of PI3K/Akt signaling pathway [61]. Therefore, we did not discard that allicin, through modulation of Nrf2-associated signaling pathways, decreases mesangial expansion and fibrosis (Figure 10).…”

Section: Discussionmentioning

confidence: 88%

Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes

et al. 2020

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This study aimed to assess the impact of allicin on the course of diabetic nephropathy. Study groups included control, diabetes, and diabetes-treated rats. Allicin treatment (16 mg/kg day/p.o.) started after 1 month of diabetes onset and was administered for 30 days. In the diabetes group, the systolic blood pressure (SBP) increased, also, the oxidative stress and hypoxia in the kidney cortex were evidenced by alterations in the total antioxidant capacity as well as the expression of nuclear factor (erythroid-derived 2)-like 2/Kelch ECH associating protein 1 (Nrf2/Keap1), hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin (Epo) and its receptor (Epo-R). Moreover, diabetes increased nephrin, and kidney injury molecule-1 (KIM-1) expression that correlated with mesangial matrix, the fibrosis index and with the expression of connective tissue growth factor (CTGF), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA). The insulin levels and glucose transporter protein type-4 (GLUT4) expression were decreased; otherwise, insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) expression was increased. Allicin increased Nrf2 expression and decreased SBP, Keap1, HIF-1α, and VEGF expression. Concurrently, nephrin, KIM-1, the mesangial matrix, fibrosis index, and the fibrotic proteins were decreased. Additionally, allicin decreased hyperglycemia, improved insulin levels, and prevented changes in (GLUT4) and IRSs expression induced by diabetes. In conclusion, our results demonstrate that allicin has the potential to help in the treatment of diabetic nephropathy. The cellular mechanisms underlying its effects mainly rely on the regulation of antioxidant, antifibrotic, and antidiabetic mechanisms, which can contribute towards delay in the progression of renal disease.

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Nrf2 signaling attenuates epithelial-to-mesenchymal transition and renal interstitial fibrosis via PI3K/Akt signaling pathways

Cited by 45 publications

References 41 publications

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Integrative microRNA and mRNA expression profiling in acute aristolochic acid nephropathy in mice

Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway

Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes

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