Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High glucose (HG)-induced apoptosis in mesangial cells (MCs) is a critical determinant during the pathogenesis of diabetic nephropathy. The signaling cascade inducing MCs apoptosis by HG involves overproduction of reactive oxygen species. Our previous studies have demonstrated that HG-induced oxidative stress is mediated by suppression of spliced/active X-box binding protein 1 (XBP1S), suggesting the importance of XBP1S in HG-induced MCs apoptosis. CHOP, an endoplasmic reticulum stress-associated proapoptotic signal, is involved in downstream of XBP1S. In the present study, we explored the effect of XBP1S in modulating HG-induced apoptosis in renal MCs and then identified the role of CHOP in these processes. Apoptosis and necrosis were quantified by flow cytometry; protein levels of XBP1S, caspase3, Bax, Bcl2, BNIP3, and CHOP were analyzed by Western blotting. The cellular localization of XBP1S was determined by immunofluorescence histochemistry. The binding of XBP1 to CHOP promoter was determined by chromatin immunoprecipitation assays. In addition, adenoviruses harboring XBP1S gene (Ad-XBP1S) were used to overexpress XBP1S, whereas the knockdown of CHOP was achieved by small interference RNA. HG suppressed nuclear distribution of XBP1S and induced apoptosis and necrosis in MCs. Ad-XBP1S infection enhanced the nuclear translocation of XBP1S and reduced MCs apoptosis and necrosis. XBP1S bound to the promoter region of CHOP and upregulated CHOP expression. Conversely, CHOP expression was reduced upon HG exposure and knockdown of CHOP increased necrosis but not apoptosis in MCs. These results suggest that XBP1S protected MCs from HG-induced apoptosis and necrosis, and CHOP participates in XBP1S-regulated necrosis but not apoptosis.
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PMID:CHOP mediates XBP1S-induced renal mesangial cell necrosis following high glucose treatment. 2585 26

Hyperglycemia upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces ROS production, inflammatory and fibrotic responses in the diabetic kidney. Dysregulation of autophagy contributes to the development of diabetic nephropathy. However, the interaction of TXNIP with autophagy/mitophagy in diabetic nephropathy is unknown. In this study, streptozotocin-induced diabetic rats were given TXNIP DNAzyme or scrambled DNAzyme for 12 weeks respectively. Fibrotic markers, mitochondrial function and mitochondrial reactive oxygen species (mtROS) were assessed in kidneys. Tubular autophagy and mitophagy were determined in kidneys from both human and rats with diabetic nephropathy. TXNIP and autophagic signaling molecules were examined. TXNIP DNAzyme dramatically attenuated extracellular matrix deposition in the diabetic kidneys compared to the control DNAzyme. Accumulation of autophagosomes and reduced autophagic clearance were shown in tubular cells of human diabetic compared to non-diabetic kidneys, which was reversed by TXNIP DNAzyme. High glucose induced mitochondrial dysfunction and mtROS production, and inhibited mitophagy in proximal tubular cells, which was reversed by TXNIP siRNA. TXNIP inhibition suppressed diabetes-induced BNIP3 expression and activation of the mTOR signaling pathway. Collectively, hyperglycemia-induced TXNIP contributes to the dysregulation of tubular autophagy and mitophagy in diabetic nephropathy through activation of the mTOR signaling pathway.
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PMID:Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway. 2738 56

Renal tubular damage caused by persistent high glucose environment has been found to contribute to diabetic nephropathy. This study explored the effects of lncRNA growth arrest-specific 5 (GAS5) on high glucose-stimulated human renal tubular epithelial HK-2 damage, as well as the possible internal molecular mechanism. Viability and apoptosis of HK-2 cells were assessed with the help of CCK-8 assay and Annexin V-FITC/PI staining, respectively. Cell transfection was used to change the expression of GAS5, miR-27a and BNIP3. We found that high glucose stimulation suppressed HK-2 cell viability but induced cell apoptosis. The expression of GAS5 was increased in HK-2 cells under high glucose environment. Silence of GAS5 mitigated the high glucose-caused HK-2 cell viability reduction and apoptosis. Overexpression of miR-27a reversed the effects of GAS5 on high glucose-stimulated HK-2 cells. Overexpression of BNIP3 aggravated the high glucose-caused HK-2 cell viability reduction, apoptosis and activation of JNK pathway. Knockdown of BNIP3 had opposite effects. In conclusion, this research further confirmed the pro-apoptotic roles of GAS5 in renal tubular epithelial cells under high glucose environment. Silence of GAS5 alleviated high glucose toxicity to human renal tubular epithelial HK-2 cells might be via down-regulating miR-27a and BNIP3, and then inactivating JNK pathway. Highlights HG suppresses HK-2 cell viability, but promotes cell apoptosis; HG enhances the expression of GAS5 in HK-2 cells; Silence of GAS5 alleviates the HG-caused HK-2 cell toxicity; miR-27a participates in the effects of GAS5 silencing on HG-stimulated HK-2 cells; BNIP3 is regulated by miR-27a and related to the HG toxicity to HK-2 cells.
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PMID:Silence of lncRNA GAS5 alleviates high glucose toxicity to human renal tubular epithelial HK-2 cells through regulation of miR-27a. 3115 92