AMP-Activated Protein Kinase Alleviates Extracellular Matrix Accumulation in High Glucose-Induced Renal Fibroblasts through mTOR Signaling Pathway

Luo, Xia; Deng, Lei; Lamsal, Laxmi Pangeni; Xu, Wei; Cheng, Xiang; Cheng, Liming

doi:10.1159/000369687

Cited by 26 publications

(19 citation statements)

References 40 publications

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“…Hyperglycemia leads to nephropathy by various mechanisms, such as increased endothelial cell permeability to albumin, hypertrophy, thickening of the basement membrane and renal fibrosis [27, 28]. In the present study, our data demonstrated that the expressions of GSK-3β, β-catenin, α-SMA, and MMP9 were increased under high glucose condition, and these changes were attenuated by paricalcitol pretreatment.…”

Section: Discussionsupporting

confidence: 65%

VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway

Guo

Zhang

et al. 2017

Cell Physiol Biochem

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Background: Diabetic nephropathy (DN) is a major cause of end-stage renal disease and proteinuria is one of the most prominent clinical manifestations. The expression of Vitamin D receptor (VDR) in patients with chronic kidney diseases was decreased, while VDR agonists could partially alleviate the proteinuria of DN in animal models. The present study was designed to determine the expression of VDR in renal tissues and its relationship with proteinuria the diabetic model db/db mice. Methods: The regulation effects of VDR on the Wnt signaling pathway were analyzed using RNA interference and VDR agonist paricalcitol. Results: With the increase in age of the db/db mice, the VDR protein and mRNA levels in renal tissues were decreased, proteinuria increased, and the protein and mRNA levels of GSK-3β of and β-catenin increased. Paricalcitol treatment resulted in the up-regulation of VDR and down-regulation of GSK-3β and β-catenin, indicating that VDR had a regulatory effect on the Wnt signaling pathway. Conclusion: VDR activation could reduce proteinuria of DN mice and alleviate high-glucose-induced injury of kidneys and podocytes by regulating the key molecules of Wnt signaling pathway.

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Section: Discussionsupporting

confidence: 65%

VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway

Guo

Zhang

et al. 2017

Cell Physiol Biochem

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“…AMPK, a serine/threonine kinase, has been considered as a metabolic switch to maintain energy homeostasis (Bolster et al, ; Luo et al, ). Meanwhile, AMPK promotes autophagy by indirect inhibiting mTOR under serum deprivation stresses (Shaw, ).…”

Section: Discussionmentioning

confidence: 99%

Autophagy regulates the apoptosis of bone marrow‐derived mesenchymal stem cells under hypoxic condition via AMP‐activated protein kinase/mammalian target of rapamycin pathway

Zhang¹,

Yang

Wang

et al. 2016

Cell Biology International

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Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been demonstrated as an ideal autologous stem cells source for cell-based therapy for myocardial infarction (MI). However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency, whereas the underlying mechanism is still poorly understood. Autophagy, a highly conserved process of cellular degradation, is required for maintaining homeostasis and normal function. Here, we investigated the potential role of autophagy on apoptosis in BM-MSCs induced by hypoxic injury. BM-MSCs, isolated from male C57BL/6 mice, were subjected to hypoxia and serum deprivation (H/SD) injury for 6, 12, and 24 h, respectively. The autophagy state was regulated by 3-methyladenine (3MA) and rapamycin administration. Furthermore, compound C was administrated to inhibit AMPK. The apoptosis induced by H/SD was determined by TUNEL assays. Meanwhile, autophagy was measured by GFP-LC3 plasmids transfection and transmission electron microscope. Moreover, protein expressions were evaluated by Western blot assay. In the present study, we found that hypoxic stress increased autophagy and apoptosis in BM-MSCs time dependently. Meanwhile, hypoxia increased the activity of AMPK/mTOR signal pathway. Moreover, increased apoptosis in BM-MSCs under hypoxia was abolished by 3-MA, whereas was aggravated by rapamycin. Furthermore, the increased autophagy and apoptosis in BM-MSCs induced by hypoxia were abolished by AMPK inhibitor compound C. These data provide evidence that hypoxia induced AMPK/mTOR signal pathway activation which regulated the apoptosis and autophagy in BM-MSCs. Furthermore, the apoptosis of BM-MSCs under hypoxic condition was regulated by autophagy via AMPK/mTOR pathway.

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“…Chronic hypoxia often occurs in the kidney tissues of many patients with CKD (18). Tubulointerstitial fibrosis leads to thickness of the tubular basement membrane and accumulation of interstitial ECM (34)(35)(36)(37). In this study, hypoxia upregulated the expression of genes related to the basement membrane.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic changes in human renal proximal tubular cells revealed under hypoxic conditions by RNA sequencing

Wang

et al. 2016

International Journal of Molecular Medicine

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Chronic hypoxia often occurs among patients with chronic kidney disease (CKD). Renal proximal tubular cells may be the primary target of a hypoxic insult. However, the underlying transcriptional mechanisms remain undefined. In this study, we revealed the global changes in gene expression in HK‑2 human renal proximal tubular cells under hypoxic and normoxic conditions. We analyzed the transcriptome of HK‑2 cells exposed to hypoxia for 24 h using RNA sequencing. A total of 279 differentially expressed genes was examined, as these genes could potentially explain the differences in HK‑2 cells between hypoxic and normoxic conditions. Moreover, 17 genes were validated by qPCR, and the results were highly concordant with the RNA seqencing results. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to better understand the functions of these differentially expressed genes. The upregulated genes appeared to be significantly enriched in the pathyway of extracellular matrix (ECM)-receptor interaction, and in paticular, the pathway of renal cell carcinoma was upregulated under hypoxic conditions. The downregulated genes were enriched in the signaling pathway related to antigen processing and presentation; however, the pathway of glutathione metabolism was downregulated. Our analysis revealed numerous novel transcripts and alternative splicing events. Simultaneously, we also identified a large number of single nucleotide polymorphisms, which will be a rich resource for future marker development. On the whole, our data indicate that transcriptome analysis provides valuable information for a more in depth understanding of the molecular mechanisms in CKD and renal cell carcinoma.

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AMP-Activated Protein Kinase Alleviates Extracellular Matrix Accumulation in High Glucose-Induced Renal Fibroblasts through mTOR Signaling Pathway

Cited by 26 publications

References 40 publications

VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway

VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway

Autophagy regulates the apoptosis of bone marrow‐derived mesenchymal stem cells under hypoxic condition via AMP‐activated protein kinase/mammalian target of rapamycin pathway

Transcriptomic changes in human renal proximal tubular cells revealed under hypoxic conditions by RNA sequencing

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