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Abstract: Berberine (BBR) was previously found to have beneficial effects on renal injury in experimental diabetic rats. However, the mechanisms underlying the effects are not fully understood. Sphingosine kinase–Sphingosine 1-phosphate (SphK–S1P) signaling pathway has been implicated in the pathogenesis of diabetic nephropathy (DN). The aim of this study was to investigate the effects of BBR on renal injury and the activation of SphK–S1P signaling pathway in alloxan-induced diabetic mice with nephropathy. Alloxan-induced diabetic mice were treated orally with BBR (300mg/kg/day) or vehicle for 12weeks. BBR inhibited the increases in fasting blood glucose, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. It also prevented renal hypertrophy, TGF-β1 synthesis, FN and Col IV accumulation. Moreover, BBR down-regulated the elevated staining, activity and levels of mRNA and protein of SphK1, and S1P production as well. These findings suggest that the inhibitory effect of BBR on the activation of SphK–S1P signaling pathway in diabetic mouse kidney is a novel mechanism by which BBR partly exerts renoprotective effects on DN. [ABSTRACT FROM AUTHOR]

Activation of casein kinase 2 (CK2) is closely linked to the body disturbance of carbohydrate metabolism and inflammatory reaction. The renal chronic inflammatory reaction in the setting of diabetes is one of the important hallmarks of diabetic renal fibrosis. However, it remains unknown whether CK2 influences the process of diabetic renal fibrosis. The current study is aimed to investigate if CK2α ameliorates renal inflammatory fibrosis in diabetes via NF-κB pathway. To explore potential regulatory mechanism of CK2α, the expression and activity of CK2α, which were studied by plasmid transfection, selective inhibitor, small-interfering RNA (siRNA) and adenovirus infection in vitro or in vivo, were analyzed by means of western blotting (WB), dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The following findings were observed: (1) Expression of CK2α was upregulated in kidneys of db/db and KKAy diabetic mice; (2) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression suppressed high glucose-induced expressions of FN and ICAM-1 in glomerular mesangial cells (GMCs); (3) Inhibition of CK2α kinase activity or knockdown of CK2α protein expression not only restrained IκB degradation, but also suppressed HG-induced nuclear accumulation, transcriptional activity and DNA binding activity of NF-κB in GMCs; (4) Treatment of TBB or CK2α RNAi adenovirus infection ameliorated renal fibrosis in diabetic animals; (5) Treatment of TBB or CK2α RNAi adenovirus infection suppressed IκB degradation and NF-κB nuclear accumulation in glomeruli of diabetic animals. This study indicates the essential role of CK2α in regulating the diabetic renal pathological process of inflammatory fibrosis via NF-κB pathway, and inhibition of CK2α may serve as a promising therapeutic strategy for diabetic nephropathy. [ABSTRACT FROM AUTHOR]

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: Both RhoA/ROCK and NF-κB signaling pathways play important roles in the pathogenesis of diabetic nephropathy (DN). However, it remains unknown whether and how RhoA/ROCK regulates NF-κB signaling in diabetic kidneys. In cultured glomerular mesangial cells (GMCs), the high glucose-activated NF-κB nuclear translocation and DNA binding activity were attenuated by ROCK inhibitor Y27632 or dominant-negative RhoA mutant, indicating that RhoA/ROCK signaling regulates high glucose-activated NF-κB pathway. Furthermore, NF-κB-regulated inflammatory factors ICAM-1 and TGF-β1 were markedly increased in high glucose-treated GMCs, leading to accumulation of fibronectin (FN), an important component of extracellular matrix (ECM), This effect was also effectively attenuated by Y27632 or dominant-negative RhoA mutant. In STZ-induced diabetic rats, treatment with ROCK inhibitor fasudil suppressed the RhoA/ROCK activation and NF-κB nuclear translocation, and significantly reduced the renal FN, ICAM-1 and TGF-β1 protein levels. Thus, the RhoA/ROCK pathway may regulate NF-κB to upregulate inflammatory genes and mediate the development of DN. [Copyright &y& Elsevier]

Abstract: Curcumin, a major polyphenol from the golden spice Curcuma longa commonly known as turmeric, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). However, the mechanisms underlying these effects remain unclear. We previously demonstrated that the sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) signaling pathway plays a pivotal role in the pathogenesis of DN. This study aims to investigate whether the renoprotective effects of curcumin on DN are associated with its inhibitory effects on the SphK1-S1P signaling pathway. Our results demonstrated that the expression and activity of SphK1 and the production of S1P were significantly down-regulated by curcumin in diabetic rat kidneys and glomerular mesangial cells (GMCs) exposed to high glucose (HG). Simultaneously, SphK1-S1P-mediated fibronectin (FN) and transforming growth factor-beta 1 (TGF-β1) overproduction were inhibited. In addition, curcumin dose dependently reduced SphK1 expression and activity in GMCs transfected with SphKWT and significantly suppressed the increase in SphK1-mediated FN levels. Furthermore, curcumin inhibited the DNA-binding activity of activator protein 1 (AP-1), and c-Jun small interference RNA (c-Jun-siRNA) reversed the HG-induced up-regulation of SphK1. These findings suggested that down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis. [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]