Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy

Abnormal and excessive growth of mesangial cells is important in the pathophysiologic processes of diabetes-associated interstitial fibrosis and glomerulosclerosis, leading to diabetic nephropathy, which eventually turns into end-stage renal disease. Sauchinone, a biologically-active lignan isolated from aerial parts of Saururus chinensis, has anti-inflammatory and anti-viral activities effects on various cell types. However, there are no studies reporting the effects of sauchinone on diabetic nephropathy. The present study aims to investigate the role of sauchinone in mesangial cell proliferation and fibrosis induced by angiotensin II, as well as the underlying mechanisms of these processes. Human renal mesangial cells were induced by angiotensin II (AngII, 10 μM) in the presence or absence of sauchinone (0.1–1 μM) and incubated for 48 h. In this study, we found that AngII induced mesangial cell proliferation, while treatment with sauchinone inhibited the cell proliferation in a dose-dependent manner. Pre-treatment with sauchinone induced down-regulation of cyclins/CDKs and up-regulation of CDK inhibitor, p21, and p27kip1 expression. In addition, AngII-enhanced expression of fibrosis biomarkers such as fibronectin, collagen IV, and connective tissue growth factor (CTGF), which was markedly attenuated by sauchinone. Sauchinone also decreased AngII-induced TGF-β1 and Smad-2, Smad-3, and Smad-4 expression. This study further revealed that sauchinone ameliorated AngII-induced mesangial inflammation through disturbing activation of inflammatory factors, and NLRP3 inflammasome, which is composed of the NLRP3 protein, procaspase-1, and apoptosis-associated speck-like protein containing a CARD (ASC). Moreover, pretreatment of sauchinone inhibited NF-κB translocation and ROS production in AngII-exposed mesangial cells. These data suggest that sauchinone has a protective effect on renal proliferation, fibrosis and inflammation. Therefore, sauchinone might be a potential pharmacological agent in prevention of AngII-induced renal damage leading to diabetic nephropathy.

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Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis through the Cascade Pathway of MEKK2–p38 MAPK–IRF-1–TRADD–Caspase 8 in Rat Thy-1 Nephritis

The Journal of Immunology ◽

10.4049/jimmunol.1600403 ◽

2016 ◽

Vol 198 (3) ◽

pp. 1104-1118 ◽

Cited By ~ 5

Author(s):

Ganqian Zhu ◽

Wen Qiu ◽

Yongting Li ◽

Chenhui Zhao ◽

Fengxia He ◽

...

Keyword(s):

P38 Mapk ◽

Cell Apoptosis ◽

Mesangial Cell ◽

Caspase 8 ◽

Glomerular Mesangial Cell

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Triptolide Suppresses Glomerular Mesangial Cell Proliferation in Diabetic Nephropathy Is Associated with Inhibition of PDK1/Akt/mTOR Pathway

International Journal of Biological Sciences ◽

10.7150/ijbs.20485 ◽

2017 ◽

Vol 13 (10) ◽

pp. 1266-1275 ◽

Cited By ~ 19

Author(s):

Fei Han ◽

Mei Xue ◽

Yunpeng Chang ◽

Xiaoyu Li ◽

Yang Yang ◽

...

Keyword(s):

Cell Proliferation ◽

Diabetic Nephropathy ◽

Mesangial Cell ◽

Mtor Pathway ◽

Glomerular Mesangial Cell ◽

Mesangial Cell Proliferation

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CXCL10 expression induced by Mxi1 inactivation induces mesangial cell apoptosis in mouse Habu nephritis

Cellular Signalling ◽

10.1016/j.cellsig.2015.01.019 ◽

2015 ◽

Vol 27 (5) ◽

pp. 943-950 ◽

Cited By ~ 1

Author(s):

Lingling Wu ◽

Xiaoniao Chen ◽

Yan Mei ◽

Quan Hong ◽

Zhe Feng ◽

...

Keyword(s):

Cell Apoptosis ◽

Mesangial Cell

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Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy

Biochemical Journal ◽

10.1042/bj3590077 ◽

2001 ◽

Vol 359 (1) ◽

pp. 77-87 ◽

Cited By ~ 60

Author(s):

Nadia Abdel WAHAB ◽

Natalia YEVDOKIMOVA ◽

Benjamin S. WESTON ◽

Terry ROBERTS ◽

Xin Jun LI ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Growth Factor ◽

Connective Tissue ◽

High Glucose ◽

Mesangial Cell ◽

Plasminogen Activator Inhibitor ◽

Tissue Growth ◽

Mrna Levels ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor

We characterized a rabbit polyclonal antibody raised against human recombinant connective tissue growth factor (CTGF). The antibody recognised a higher molecular mass form (approx. 56kDa) of CTGF in mesangial cell lysates as well as the monomeric (36–38kDa) and lower molecular mass forms (< 30kDa) reported previously. Immunohistochemistry detected CTGF protein in glomeruli of kidneys of non-obese diabetic mice 14 days after the onset of diabetes, and this was prominent by 70 days. CTGF protein is also present in glomeruli of human patients with diabetic nephropathy. No CTGF was detected in either normal murine or human glomeruli. Transient transfection of a transformed human mesangial cell line with a CTGF–V5 epitope fusion protein markedly increased fibronectin and plasminogen activator inhibitor-1 synthesis in cultures maintained in normal glucose (4mM) conditions; a CTGF-antisense construct reduced the elevated synthesis of these proteins in high glucose (30mM) cultures. Culture of primary human mesangial cells for 14 days in high glucose, or in low glucose supplemented with recombinant CTGF or transforming growth factor β1, markedly increased CTGF mRNA levels and fibronectin synthesis. However, whilst co-culture with a CTGF-antisense oligonucleotide reduced the CTGF mRNA pool by greater than 90% in high glucose, it only partially reduced fibronectin mRNA levels and synthesis. A chick anti-CTGF neutralizing antibody had a similar effect on fibronectin synthesis. Thus both CTGF and CTGF-independent pathways mediate increased fibronectin synthesis in high glucose. Nevertheless CTGF expression in diabetic kidneys is likely to be a key event in the development of glomerulosclerosis by affecting both matrix synthesis and, potentially through plasminogen activator inhibitor-1, its turnover.

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