The MCP-1/CCR2 axis in podocytes is involved in apoptosis induced by diabetic conditions

Nam, Bo Young; Paeng, Jisun; Kim, Seung Hye; Lee, Sun Ha; Kim, Do Hee; Kang, Hye Young; Li, Jin Ji; Kwak, Seung Jae; Park, Sun-Hee; Yoo, Tae‐Hyun; Han, Seung Hyeok; Kim, Yon Su; Kang, Shin Wook

doi:10.1007/s10495-011-0661-6

Cited by 35 publications

(34 citation statements)

References 40 publications

(67 reference statements)

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“…Some debate exists about which mechanism, namely podocyte apoptosis or detachment, is quantitatively more important for podocyte loss in glomerulopathies such as diabetic nephropathy. Although TGF-β has been shown to induce podocyte apoptosis in vitro and in vivo, the apoptosis rates detected in vivo are low (Nam et al 2011). The studies of Wharram et al (2005) have demonstrated that high rates of podocyte loss are necessary to cause glomerular scarring: depletion of podocytes by up to 40% results in only minor changes in the glomerular structure and moderate proteinuria without measurable changes in renal function, with podocyte depletion of over 40% being required before a detectable decrease in renal function can be observed.…”

Section: Effect Of Tgf-β On Podocytesmentioning

confidence: 99%

Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects

2011

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Transforming growth factor beta (TGF-β) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-β induces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF-β has been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re-examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-β participates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD.

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Section: Effect Of Tgf-β On Podocytesmentioning

confidence: 99%

Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects

2011

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“…17,19 Recently, we also found that MCP-1 directly induced podocyte apoptosis. 18 In addition, MCP-1 itself induced intercellular adhesion molecule-1 and fibronectin expression in cultured mesangial cells. 14 Moreover, some investigators have provided evidence that MCP-1 may be directly involved in ECM synthesis using animal models of experimental glomerulonephritis 15 and diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 97%

“…18 The band densities were measured using TINA image software (Raytest, Straubenhardt, Germany), and the changes in the optical densities of bands from the treated groups relative to NG cells or C peritoneum were used in the analysis.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…[14][15][16] In addition, several recent studies have shown that there may be an intrinsic regulatory loop between MCP-1 and TGF-b1. [17][18][19][20][21][22] To our knowledge, however, no study has investigated if there is a direct association between the MCP-1/ CCR2 system and TGF-b1 in PMCs. Moreover, the direct effect of MCP-1 on EMT and ECM synthesis has never been elucidated in these cells.…”

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confidence: 99%

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The monocyte chemoattractant protein-1 (MCP-1)/CCR2 system is involved in peritoneal dialysis-related epithelial–mesenchymal transition of peritoneal mesothelial cells

Lee

Kang

Kim

et al. 2012

Laboratory Investigation

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Epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) has a role in the process of peritoneal fibrosis (PF), a serious complication in peritoneal dialysis (PD) patients. Even though monocyte chemoattractant protein-1 (MCP-1) was demonstrated to directly increase extracellular matrix (ECM) synthesis, the role of the MCP-1/CCR2 system in PD-related EMT and ECM synthesis in cultured human PMCs (HPMCs) and in an animal model of PD has never been elucidated. In vitro, HPMCs were exposed to 5.6 mM glucose (NG), NG þ MCP-1 (10 ng/ml) (NG þ MCP-1), or 100 mM glucose (HG) with or without CCR2 inhibitor (RS102895) (CCR2i) or a dominant-negative mutant MCP-1-expressing lentivirus (LV-mMCP-1). In vivo, PD catheters were inserted into 60 Sprague-Dawley rats, and saline (Control, C) (N ¼ 30) or 4.25% PD solution (PD) (N ¼ 30) was infused for 4 weeks. Twenty rats from each group were treated with empty LV or LVmMCP-1 intraperitoneally. Snail, E-cadherin, a-smooth muscle actin (a-SMA), and fibronectin protein expression in HPMCs and the peritoneum was evaluated by western blot analysis. Compared with NG cells, Snail, a-SMA, and fibronectin expression was significantly increased, while E-cadherin expression was significantly decreased in HPMCs exposed to HG and NG þ MCP-1, and these changes were significantly abrogated by CCR2i (Po0.05). In addition, MCP-1-induced EMT was significantly attenuated by anti-TGF-b1 antibody. In PD rats, Snail and fibronectin expression was significantly increased in the peritoneum, whereas the ratios of E-cadherin/a-SMA protein expression were significantly decreased (Po0.05). The thickness of the peritoneum and the intensity of Masson's trichrome staining in the peritoneum were also significantly higher in PD rats than in C rats (Po0.05). These changes in PD rats were significantly abrogated by LV-mMCP-1. These findings suggest that the MCP-1/CCR2 system is directly involved in PD-related EMT and ECM synthesis and that this is mediated, at least in part, via TGF-b1.

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“…Lentivirus vectors and liposomes are widely applied for the transduction of siRNA into different types of cultured renal cells. For example, silencing ccr2 using its siRNA delivered by a lentivirus significantly ameliorated MCP-1 induced podocyte apoptosis under diabetic conditions [23]. Similarly, degradation of FoxO1 by transfecting its siRNA via lentiviral vectors overrode the limited cell cycle and stimulated proliferation of glomerular mesangial cells [24].…”

Section: Sirna Deliverymentioning

confidence: 99%

Fighting against kidney diseases with small interfering RNA: opportunities and challenges

et al. 2015

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The significant improvements in siRNA therapy have been achieved, which have great potential applications in humans. The kidney is a comparatively easy target organ of siRNA therapy due to its unique structural and functional characteristics. Here, we reviewed recent achievements in siRNA design, delivery and application with focuses on kidney diseases, in particular kidney transplant-related injuries. In addition, the strategy for increasing serum stability and immune tolerance of siRNA was also discussed. At last, the future challenges of siRNA therapy including organ/tissue/cell-specific delivery and time-controlled silence, as well as selecting therapeutic targets, were addressed as well.

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The MCP-1/CCR2 axis in podocytes is involved in apoptosis induced by diabetic conditions

Cited by 35 publications

References 40 publications

Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects

Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects

The monocyte chemoattractant protein-1 (MCP-1)/CCR2 system is involved in peritoneal dialysis-related epithelial–mesenchymal transition of peritoneal mesothelial cells

Fighting against kidney diseases with small interfering RNA: opportunities and challenges

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