Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

Lázaro, Iolanda; Oguiza, Ainhoa; Recio, Carlota; Mallavia, Beñat; Madrigal‐Matute, Julio; Blanco, Julia; Egido, Jesús; Martin-Ventura, José Luis; Gómez-Guerrero, Carmen

doi:10.2337/db14-1926

Cited by 67 publications

(62 citation statements)

References 50 publications

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“…This finding was consistent with a known mechanism of NF-κB in diabetic renal inflammation918192021222324. Indeed, we have previously reported that human CRP can promote renal inflammation by activating NF-κB signaling via the CD32/64-dependent mechanism in a mouse model of type 1 diabetic nephropathy induced in CRPtg mice and in vitro 9.…”

Section: Discussionsupporting

confidence: 89%

C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway

You

Huang

Chen

et al. 2016

Sci Rep

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C-reactive protein (CRP) is associated with progressive diabetic nephropathy in patients with type-2 diabetes (T2DN). However, role of CRP in T2DN remains unclear. We report here that CRP is pathogenic in T2DN in db/db mice that express human CRP (CRPtg-db/db). Compared to the littermate db/db mice, CRPtg-db/db developed more severe T2DN, showing higher levels of fasting blood glucose and microalbuminuria and more progressive renal inflammation and fibrosis. Enhanced T2DN in CRPtg-db/db mice were associated with over-activation of CRP-CD32b, NF-κB, TGF-β/Smad3, and mTOR signaling. Further studies in vitro defined that CRP activated Smad3 directly at 15 mins via the CD32b- ERK/p38 MAP kinase crosstalk pathway and indirectly at 24 hours through a TGF-β1-dependent mechanism. Importantly, CRP also activated mTOR signaling at 30 mins via a Smad3-dependent mechanism as Smad3 bound mTOR physically and CRP-induced mTOR signaling was abolished by a neutralizing CD32b antibody and a specific Smad3 inhibitor. Finally, we also found that CRP induced renal fibrosis through a CD32b-Smad3-mTOR pathway because blocking mTOR signaling with rapamycin inhibited CRP-induced CTGF and collagen I expression. Thus, CRP is pathogenic in T2DN. CRP may promote CD32b- NF-κB signaling to mediate renal inflammation; whereas, CRP may enhance renal fibrosis in T2DN via CD32b-Smad3-mTOR signaling.

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Section: Discussionsupporting

confidence: 89%

C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway

You

Huang

Chen

et al. 2016

Sci Rep

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“…The present study showed that the DM group had increased protein and mRNA levels of NF-κB p65 and its active form phospho-NF-κB p65. The result was consistent with previous studies, which found increased NF-κB activity in diabetic animals (5,7,30). IκBα is an inhibitor of the activation of NF-κB p65, which can suppress the phosphorylation of NF-κB p65.…”

Section: Discussionsupporting

confidence: 83%

Involvement of the NF-κB signaling pathway in the renoprotective effects of isorhamnetin in a type 2 diabetic rat model

et al. 2016

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Abstract. The aim of the present study was to investigate the renoprotective effects of isorhamnetin (ISO) in type 2 diabetic rats and its effects on the nuclear factor-κB (NF-κB) signaling pathway, which is associated with diabetic nephropathy. The type 2 diabetic rat model was established by a high-fat diet plus streptozocin injection and the rats were subsequently treated with two dosages of ISO, respectively. The levels of blood glucose were determined. Urinary osteopontin, kidney injury molecule-1 (KIM-1) and albumin were measured to evaluate the renal function of the rats. Renal NF-κB signaling activity was assessed by measuring the levels of NF-κB p65, phospho-NF-κB p65, inhibitor of NF-κB (IκBα) and phospho-IκBα, and the NF-κB p65 DNA-binding activity. Downstream inflammatory mediators [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-β1 (TGF-β1)] of the NF-κB signaling pathway were investigated to evaluate the renal inflammatory response. Renal levels of malondialdehyde and total superoxide dismutase were detected to access the oxidative stress. Furthermore, glomerular mesangial cells (GMCs) were treated with lipopolysaccharide and ISO. In the cellular experiment, the NF-κB signaling activity, levels of TNF-α, IL-1β, IL-6, ICAM-1 and TGF-β1, and oxidative stress were also investigated. The results showed that ISO decreased the levels of urinary osteopontin, KIM-1 and albumin. ISO also inhibited the NF-κB signaling activity, decreased the production of inflammatory mediators and attenuated oxidative stress in diabetic rats and GMCs. The present investigations revealed that ISO had ameliorative effects on diabetes-induced renal damage and the activity may be associated with the negative regulation of NF-κB signaling pathway.

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“…The diabetic rats treated with AG showed significantly lower TNF‐α, IL‐6, and IL‐1β serum levels, as well as the effect of high dose group better than positive group. Because the NF‐κB signaling pathway plays a key role in renal inflammation in DN (Lazaro et al, ), we also investigated whether AG affects renal NF‐κB signaling in diabetic rats. As shown in Figure d, compared with the control rats, the diabetic rats showed 2.37‐fold and 2.53‐fold increased expression of renal phospho‐IκBα (p‐IκBα) and p‐NF‐κBp65, respectively, and 0.39‐fold decreased IκBα expression.…”

Section: Resultsmentioning

confidence: 99%

A branched arabinoglucan from Angelica sinensis ameliorates diabetic renal damage in rats

Sui

Liu

Tian

et al. 2019

Phytotherapy Research

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Diabetic nephropathy (DN) is a major complication in long‐standing diabetic patients, and effective therapies are required. In this study, we examined the effects and mechanisms of an arabinoglucan (AG) isolated from Angelica sinensis on DN, which was induced in rats by streptozotocin. The rats were intraperitoneally treated with AG for 8 weeks. Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen and proteinuria, along with marked enhanced mesangial expansion. All of these abnormalities were reversed by the AG. Overproliferation of glomerular mesangial cells (GMCs) was halted by AG treatment, and inflammation mediators were attenuated. Furthermore, the AG significantly inhibited the expression of nuclear factor‐κB (NF‐κB) and receptor for advanced glycation end products (RAGE), both in diabetic kidneys and in high glucose‐induced GMCs. Using an NF‐κB inhibitor, RAGE siRNA and RAGE‐overexpressing plasmid, we further demonstrated that the AG inhibited GMC viability mediated by RAGE/NF‐κB signaling pathway. More importantly, we show that the AG can directly interact with RAGE and disrupt RAGE binding to advanced glycation end products using microscale thermophoresis. These findings suggest that this AG, acting as a RAGE antagonist, is a promising agent for the prevention and treatment of DN.

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Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

Cited by 67 publications

References 50 publications

C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway

C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway

Involvement of the NF-κB signaling pathway in the renoprotective effects of isorhamnetin in a type 2 diabetic rat model

A branched arabinoglucan from Angelica sinensis ameliorates diabetic renal damage in rats

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