Circular RNA circRNA_15698 aggravates the extracellular matrix of diabetic nephropathy mesangial cells via miR-185/TGF-β1

2018 ◽  
Vol 234 (2) ◽  
pp. 1469-1476 ◽  
Author(s):  
Wei Hu ◽  
Qing Han ◽  
Lei Zhao ◽  
Li Wang
Keyword(s):  
Extracellular Matrix ◽  
Diabetic Nephropathy ◽  
Mesangial Cells ◽  
Circular Rna ◽  
Tgf Β1

scholarly journals Ergosterol Ameliorates Diabetic Nephropathy by Attenuating Mesangial Cell Proliferation and Extracellular Matrix Deposition via the TGF-β1/Smad2 Signaling Pathway

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 483 ◽  
Author(s):  
Zhonghua Dong ◽  
Yueyue Sun ◽  
Guangwei Wei ◽  
Siying Li ◽  
Zhongxi Zhao
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Diabetic Nephropathy ◽  
Signaling Pathway ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Diabetic Mice ◽  
Mesangial Cell Proliferation ◽  
Tgf Β1

(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 μM ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells; Furthermore, ergosterol markedly improved transforming growth factor-β1 (TGF-β1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-β1/Smad2 signaling pathway.

HB-EGF release mediates glucose-induced activation of the epidermal growth factor receptor in mesangial cells

2011 ◽  
Vol 300 (4) ◽  
pp. F921-F931 ◽  
Author(s):  
L. Uttarwar ◽  
F. Peng ◽  
D. Wu ◽  
S. Kumar ◽  
B. Gao ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Mesangial Cells ◽  
Growth Factor Receptor ◽  
Egfr Transactivation ◽  
Akt Activation ◽  
Epidermal Growth ◽  
Tgf Β1

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We showed that transactivation of the epidermal growth factor receptor (EGFR) is an important mediator of matrix upregulation in mesangial cells (MC) in response to high glucose (HG). Here, we study the mechanism of EGFR transactivation. In primary MC, EGFR transactivation by 1 h of HG (30 mM) was unaffected by inhibitors of protein kinase C, reactive oxygen species, or the angiotensin II AT1 receptor. However, general metalloprotease inhibition, as well as specific inhibitors of heparin-binding EGF-like growth factor (HB-EGF), prevented both EGFR and downstream Akt activation. HB-EGF was released into the medium by 30 min of HG, and this depended on metalloprotease activity. One of the metalloproteases shown to cleave proHB-EGF is ADAM17 (TACE). HG, but not an osmotic control, activated ADAM17, and its inhibition prevented EGFR and Akt activation and HB-EGF release into the medium. siRNA to either ADAM17 or HB-EGF prevented HG-induced EGFR transactivation. We previously showed that EGFR/Akt signaling increases transforming growth factor (TGF)-β1 transcription through the transcription factor activator protein (AP)-1. HG-induced AP-1 activation, as assessed by EMSA, was abrogated by inhibitors of metalloproteases, HB-EGF and ADAM17. HB-EGF and ADAM17 siRNA also prevented AP-1 activation. Finally, these inhibitors and siRNA prevented TGF-β1 upregulation by HG. Thus, HG-induced EGFR transactivation in MC is mediated by the release of HB-EGF, which requires activity of the metalloprotease ADAM17. The mechanism of ADAM17 activation awaits identification. Targeting upstream mediators of EGFR transactivation including HB-EGF or ADAM17 provides novel therapeutic targets for the treatment of diabetic nephropathy.

scholarly journals CircSMAD4 alleviates high glucose-induced inflammation, extracellular matrix deposition and apoptosis in mouse glomerulus mesangial cells by relieving miR-377-3p-mediated BMP7 inhibition

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Rina Wu ◽  
Zheli Niu ◽  
Guangwei Ren ◽  
Lin Ruan ◽  
Lijun Sun
Keyword(s):  
Extracellular Matrix ◽  
High Glucose ◽  
Mesangial Cells ◽  
Circular Rna ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Matrix Deposition

Abstract Background Diabetic nephropathy (DN) is a common complication of diabetes mellitus. Accumulating studies suggest that the deregulation of circular RNA (circRNA) is involved in DN pathogenesis. This study aimed to investigate the role of circSMAD4 in DN models. Methods Mice were treated with streptozotocin to establish DN models in vivo. Mouse glomerulus mesangial cells (SV40-MES13) were treated with high glucose to establish DN models in vitro. The expression of circSMAD4, miR-377-3p and bone morphogenetic protein 7 (BMP7) mRNA was measured by quantitative real-time PCR (qPCR). The releases of inflammatory factors were examined by ELISA. The protein levels of fibrosis-related markers, apoptosis-related markers and BMP7 were checked by western blot. Cell apoptosis was monitored by flow cytometry assay. The predicted relationship between miR-377-3p and circSMAD4 or BMP7 was validated by dual-luciferase reporter assay or pull-down assay. Results CircSMAD4 was poorly expressed in DN mice and HG-treated SV40-MES13 cells. HG induced SV40-MES13 cell inflammation, extracellular matrix (ECM) deposition and apoptosis. CircSMAD4 overexpression alleviated, while circSMAD4 knockdown aggravated HG-induced SV40-MES13 cell injuries. MiR-377-3p was targeted by circSMAD4, and miR-377-3p enrichment partly reversed the effects of circSMAD4 overexpression. BMP7 was a target of miR-377-3p, and circSMAD4 regulated BMP7 expression by targeting miR-377-3p. MiR-377-3p overexpression aggravated HG-induced injuries by suppressing BMP7. Conclusion CircSMAD4 alleviates HG-induced SV40-MES13 cell inflammation, ECM deposition and apoptosis by relieving miR-377-3p-mediated inhibition on BMP7 in DN progression.

scholarly journals Buyang Huanwu Decoction protects against STZ-induced diabetic nephropathy by inhibiting TGF-β/Smad3 signaling-mediated renal fibrosis and inflammation

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Weifeng Wu ◽  
Yifan Wang ◽  
Haidi Li ◽  
Haiyong Chen ◽  
Jiangang Shen
Keyword(s):  
Renal Function ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Renal Fibrosis ◽  
Mesangial Cells ◽  
Buyang Huanwu Decoction ◽  
Active Compounds ◽  
Renal Inflammation ◽  
Pas Staining ◽  
Tgf Β1

Abstract Background Buyang Huanwu Decoction (BHD) is a classical Chinese Medicine formula empirically used for diabetic nephropathy (DN). However, its therapeutic efficacies and the underlying mechanisms remain obscure. In our study, we aim to evaluate the renoprotective effect of BHD on a streptozotocin (STZ)-induced diabetic nephropathy mouse model and explore the potential underlying mechanism in mouse mesangial cells (MCs) treated with high glucose in vitro, followed by screening the active compounds in BHD. Methods Mice were received 50 mg/kg streptozotocin (STZ) or citrate buffer intraperitoneally for 5 consecutive days. BHD was intragastrically administrated for 12 weeks starting from week 4 after the diabetes induction. The quality control and quantitative analysis of BHD were studied by high-performance liquid chromatography (HPLC). Renal function was evaluated by urinary albumin excretion (UAE) using ELISA. The mesangial matrix expansion and renal fibrosis were measured using periodic acid-schiff (PAS) staining and Masson Trichrome staining. Mouse mesangial cells (MCs) were employed to study molecular mechanisms. Results We found that the impaired renal function in diabetic nephropathy was significantly restored by BHD, as indicated by the decreased UAE without affecting the blood glucose level. Consistently, BHD markedly alleviated STZ-induced diabetic glomerulosclerosis and tubulointerstitial injury as shown by PAS staining, accompanied by a reduction of renal inflammation and fibrosis. Mechanistically, BHD inhibited the activation of TGF-β1/Smad3 and NF-κB signaling in diabetic nephropathy while suppressing Arkadia expression and restoring renal Smad7. We further found that calycosin-7-glucoside (CG) was one of the active compounds from BHD, which significantly suppressed high glucose-induced inflammation and fibrosis by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways in mesangial cells. Conclusion BHD could attenuate renal fibrosis and inflammation in STZ-induced diabetic kidneys via inhibiting TGF-β1/Smad3 and NF-κB signaling while suppressing the Arkadia and restoring renal Smad7. CG could be one of the active compounds in BHD to suppress renal inflammation and fibrosis in diabetic nephropathy.

scholarly journals Lovastatin Inhibits Transforming Growth Factor-β1 Expression in Diabetic Rat Glomeruli and Cultured Rat Mesangial Cells

2000 ◽  
Vol 11 (1) ◽  
pp. 80-87
Author(s):  
SUNG IL KIM ◽  
DONG CHEOL HAN ◽  
HI BAHL LEE
Keyword(s):  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Diabetic Rats ◽  
Kidney Weight ◽  
Urine Albumin Excretion ◽  
Urine Albumin ◽  
Ecm Proteins ◽  
Tgf Β1

Abstract. Diabetic nephropathy is a leading cause of end-stage renal disease and is characterized by excessive deposition of extracellular matrix (ECM) proteins in the glomeruli. Transforming growth factor-β (TGF-β) is the major mediator of excessive accumulation of ECM proteins in diabetic nephropathy through upregulation of genes encoding ECM proteins as well as downregulation of genes for ECM-degrading enzymes. It has been shown that lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, delays the onset and progression of different models of experimental nephropathy. To evaluate the effect of lovastatin on the development and progression of diabetic nephropathy, streptozotocin-induced diabetic rats were studied for 12 mo. In untreated diabetic rats, there were significant increases in blood glucose, urine albumin excretion, kidney weight, glomerular volume, and TGF-β1 mRNA expression in the glomeruli compared with normal control rats treated with citrate buffer only. Treatment with lovastatin in diabetic rats significantly suppressed the increase in urine albumin excretion, kidney weight, glomerular volume, and TGF-β1 mRNA expression despite high blood glucose levels. To elucidate the mechanisms of the renal effects of lovastatin, rat mesangial cells were cultured under control (5.5 mM) or high (30 mM) glucose with lovastatin alone, mevalonate alone, or with both. Under high glucose, TGF-β1 and fibronectin mRNA and proteins were upregulated. These high glucose-induced changes were suppressed by lovastatin (10 μM) and nearly completely restored by mevalonate (100 μM). These results suggest that lovastatin has a direct cellular effect independent of a cholesterol-lowering effect and delays the onset and progression of diabetic nephropathy, at least in part, through suppression of glomerular expression of TGF-β1.

Circular RNA Circ_0000064 promotes the proliferation and fibrosis of mesangial cells via miR-143 in diabetic nephropathy

Gene ◽  
2020 ◽  
Vol 758 ◽  
pp. 144952 ◽  
Author(s):  
Xiaoxu Ge ◽  
Liuqing Xi ◽  
Qianqian Wang ◽  
Huihua Li ◽  
Lili Xia ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mesangial Cells ◽  
Circular Rna
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