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We previously demonstrated that activation of sphingosine kinase 1 (SphK1)- sphingosine 1- phosphate (S1P) signaling pathway by high glucose (HG) plays a pivotal role in increasing the expression of fibronectin (FN), an important fibrotic component, by promoting the DNA-binding activity of transcription factor activator protein 1 (AP-1) in glomerular mesangial cells (GMCs) under diabetic conditions. As a multi-target anti-oxidative drug, polydatin (PD) has been shown to have renoprotective effects on experimental diabetes. However, whether PD could resist diabetic nephropathy (DN) by regulating SphK1-S1P signaling pathway needs further investigation. Here, we found that PD significantly reversed the upregulated FN and ICAM-1 expression in GMCs exposed to AGEs. Simultaneously, PD dose-dependently inhibited SphK1 levels at the protein expression and kinase activity and attenuated S1P production under AGEs treatment conditions. In addition, PD reduced SphK activity in GMCs transfected with wild-type SphK WT plasmid and significantly suppressed SphK1-mediated increase of FN and ICAM-1 levels under normal conditions. Furthermore, we found that the AGEs-induced upregulation of phosphorylation of c-Jun at Ser63 and Ser73 and c-Fos at Ser32, DNA-binding activity and transcriptional activity of AP-1 were blocked by PD. In comparison with db/db model group, PD treatment suppressed SphK1 levels (mRNA, protein expression, and activity) and S1P production, reversed the upregulation of FN, ICAM-1, c-Jun, and c-Fos in the kidney tissues of diabetic mice, and finally ameliorated renal injury in db/db mice. These findings suggested that the downregulation of SphK1-S1P signaling pathway is probably a novel mechanism by which PD suppressed AGEs-induced FN and ICAM-1 expression and improved renal dysfunction of diabetic models. [ABSTRACT FROM AUTHOR]

Highlights: [•] We confirm the importance of berberine in ECM protein accumulation in DN. [•] We examine the regulation of RhoA/ROCK signaling by berberine in DN. [•] Berberine regulates NF-κB in DN. [Copyright &y& Elsevier]

Abstract: A number of studies have recently demonstrated the involvement of nuclear factor-kappa B (NF-κB) activation and the subsequent coordinated inflammatory responses in the pathogenesis of diabetic nephropathy (DN). Polydatin has been shown to have the ability of anti-adhesive inflammation. However, the possible protective and beneficial effects of polydatin on DN via suppressing inflammatory damage and extracellular matrix (ECM) accumulation are not fully elucidated. We found that the polydatin could inhibit the induction and activity of NF-κB, and meanwhile ameliorating ECM accumulation in streptozotocin-diabetic rats. We aimed to investigate the effect of polydatin on fibronectin (FN) protein expression, and to elucidate its potential mechanism involving the NF-κB inflammatory signaling pathway in rat glomerular mesangial cells (GMCs) cultured under high glucose. The results revealed that polydatin significantly suppressed high glucose-induced FN production, inhibited NF-κB nuclear translocation, reduced the DNA-binding activity of NF-κB, as well as decreased the protein expression of ICAM-1 and TGF-β in GMCs. These findings suggested that polydatin significantly represses high glucose-induced FN expression in rat GMCs, which may be closely related to its inhibition of the NF-κB signaling pathway. Hence, we elucidated the potential mechanisms of the anti-inflammatory effects and ECM accumulation alleviation of polydatin in GMCs of DN in vitro. [Copyright &y& Elsevier]

Abstract: Accumulation of extracellular matrix including fibronectin in mesangium is one of the major pathologic characteristics in diabetic nephropathy. In the current study, we explored role of sphingosine-1-phosphate (S1P) receptor in fibronectin expression and underlying molecular mechanism. Among five S1P receptors the mRNA level of S1P2 receptor was the most abundant in kidney of diabetic rats and mesangial cells under high glucose condition. S1P augmentation of fibronectin was significantly inhibited by S1P2 receptor antagonist JTE-013 and S1P2-siRNA. S1P-stimulated fibronectin expression was remarkably blocked by ERK1/2 inhibitor PD98059 and p38MAPK inhibitor SB203580. Phospho-ERK1/2 and phospho-p38MAPK level induced by S1P were markedly abrogated by JTE-013 and S1P2-siRNA. In conclusion, S1P2 receptor was significantly up-regulated under diabetic condition. S1P2 receptor mediated fibronectin expression through the activation of S1P-S1P2-MAPK (ERK1/2 and p38MAPK) axis in mesangial cells under high glucose condition, suggesting that it might be a potential therapeutic target for diabetic nephropathy treatment. [Copyright &y& Elsevier]

Abstract: Our previous findings demonstrated that emodin could improve the renal function in rats with diabetic nephropathy, but little is known about its molecular mechanisms. In this study, we investigated the effects of emodin on high glucose (HG)-induced cell proliferation and fibronectin (FN) protein expression in rat mesangial cells, and explored the possible mechanism. Cell proliferation and cell cycle were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assay, respectively. The protein levels of FN, p-p38MAPK, t-p38MAPK, p-CREB, PPARγ, and CTGF in rat mesangial cells were detected by Western blot. Our results demonstrated that emodin significantly suppressed HG-induced cell proliferation and arrested cell cycle progress. Protein expression of FN, phospho-p38MAPK, phospho-CREB and CTGF was markedly reduced, and PPARγ protein level was significantly increased after emodin treatment. In conclusion, emodin suppressed HG-induced cell proliferation and FN expression in rat mesangial cells through inhibiting the p38MAPK pathway involved CREB, PPAPγ and CTGF, suggesting a potential role of emodin in the treatment of diabetic nephropathy. [Copyright &y& Elsevier]