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Reduced beta 2 glycoprotein I improve diabetic nephropathy via inhibiting TGF-?1-p38 MAPK pathway.

ABSTRACT: PURPOSE:Beta 2 glycoprotein I (?2GPI) has been shown the positive effect on diabetic atherosclerosis and retinal neovascularization. ?2GPI can be reduced by thioredoxin-1, resulting in the reduced state of ?2GPI. The possible protective effects of ?2GPI and reduced ?2GPI on diabetic nephropathy (DN) are not fully elucidated. The purpose of this study was to test a hypothesis that ?2GPI and reduced ?2GPI would improve DN in streptozotocin (STZ) induced diabetic mice and high-glucose (HG) exposed rat mesangial cell (RMC). METHODS:The STZ-induced Balb/c mice and HG exposed RMCs were administrated with ?2-GPI and reduced ?2-GPI at different time and concentrations gradient respectively. The changes of glomerular structure and expression of collagen IV, TGF-?1, p38 MAPK and phospho-p38 MAPK in renal cortical and mesangial cells were observed by immunohistochemical techniques, quantitative real-time PCR and western blot with or without the treatment of ?2-GPI and reduced ?2-GPI. RESULTS:?2GPI and reduced ?2GPI improved early clinical and pathological changes of DN in STZ-diabetic mice. Treatment with ?2GPI and reduced ?2GPI in the STZ-diabetic mice and HG exposed RMCs resulted in decrease expression levels of TGF-?1 and collagen IV, with concomitant decrease in phospho-p38 MAPK expression. CONCLUSIONS:?2GPI and reduced ?2GPI improved renal structural damage and kidney function. The renoprotective and antifibrosis effects of ?2GPI and reduced ?2GPI on DN were closely associated with suppressing the activation of the TGF-?1-p38 MAPK pathway.

SUBMITTER: Wang T

PROVIDER: S-EPMC4509168 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Reduced beta 2 glycoprotein I improve diabetic nephropathy via inhibiting TGF-β1-p38 MAPK pathway.

Wang Tong T Chen Si-Si SS Chen Rui R Yu De-Min DM Yu Pei P

International journal of clinical and experimental medicine 20150515 5

<h4>Purpose</h4>Beta 2 glycoprotein I (β2GPI) has been shown the positive effect on diabetic atherosclerosis and retinal neovascularization. β2GPI can be reduced by thioredoxin-1, resulting in the reduced state of β2GPI. The possible protective effects of β2GPI and reduced β2GPI on diabetic nephropathy (DN) are not fully elucidated. The purpose of this study was to test a hypothesis that β2GPI and reduced β2GPI would improve DN in streptozotocin (STZ) induced diabetic mice and high-glucose (HG) ...[more]

PMID: 26221223

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Project description:BackgroundBuyang 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.MethodsMice 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.ResultsWe 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.ConclusionBHD 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.

Project description:Hyperglycemia induces p38 MAPK-mediated renal proximal tubular cell (RPTC) apoptosis. The current study hypothesized that alteration of the Akt signaling pathway by hyperglycemia may contribute to p38 MAPK activation and development of diabetic nephropathy. Immunoblot analysis demonstrated a hyperglycemia-induced increase in Akt phosphorylation in diabetic kidneys at 1 mo, peaking at 3 mo, and dropping back to baseline by 6 mo. Immunohistochemical staining with anti-pAkt antisera localized Akt phosphorylation to renal tubules. Maximal p38 MAPK phosphorylation was detected concomitant with increase in terminal uridine deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and caspase-3 activity in 6-mo diabetic kidneys. Exposure of cultured RPTCs to high glucose (HG; 22.5 mM) significantly increased Akt phosphorylation at 3, 6, and 9 h, and decreased thereafter. In contrast, p38 MAPK phosphorylation was detected between 9 and 48 h of HG treatment. Increased p38 MAPK activation at 24 and 48 h coincided with increased apoptosis, demonstrated by increased caspase-3 activity at 24 h and increased TUNEL-positive cells at 48 h of HG exposure. Blockade of p38 cascade with SB203850 inhibited HG-induced caspase-3 activation and TUNEL-positive cells. Overexpression of constitutively active Akt abrogated HG-induced p38 MAPK phosphorylation and RPTC apoptosis. In addition, blockade of the phosphatidylinositol-3 kinase/Akt pathway with LY294002 and silencing of Akt expression with Akt small interfering RNA induced p38 MAPK phosphorylation in the absence of HG. These results collectively suggest that downregulation of Akt activation during long-term hyperglycemia contributes to enhanced p38 MAPK activation and RPTC apoptosis. Mechanism of downregulation of Akt activation in 6-mo streptozotocin diabetic kidneys was attributed to decreased Akt-heat shock protein (Hsp) 25, Akt-p38 interaction, and decreased PTEN activity. Thus PTEN or Hsp25 could serve as potential therapeutic targets to modulate Akt activation and control p38 MAPK-mediated diabetic complications.

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Reduced beta 2 glycoprotein I improve diabetic nephropathy via inhibiting TGF-?1-p38 MAPK pathway.

Publications

Reduced beta 2 glycoprotein I improve diabetic nephropathy via inhibiting TGF-β1-p38 MAPK pathway.

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