Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

Yang, Shi‐Ming; Ka, Shuk‐Man; Wu, Hua; Yeh, Yu Chuan; Kuo, Chien-Nan; Hua, Kuo Feng; Shi, Guey Yueh; Hung, Yi Jen; Hsiao, Fone-Ching; Yang, Sung Sen; Shieh, Yi‐Shing; Lin, Shih Hua; Wei, Chyou Wei; Lee, Jeng Shin; Yang, Chu Yi; Chen, Ann

doi:10.1007/s00125-013-3115-6

Cited by 98 publications

(81 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 93%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 93%

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…[15][16][17] Of note, a mechanistic relevance of inflammasome activation in animal models of dNP has recently been established. 3 Furthermore, a recent observational study suggests that inhibition of inflammasome signaling improves renal function (on the basis of a decline in serum creatinine) in patients with established dNP.…”

mentioning

confidence: 99%

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Shahzad

Bock

Al‐Dabet

et al. 2016

JASN

View full text Add to dashboard Cite

Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1b), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucosestressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.

show abstract

“…[16][17][18] Our previous works have demonstrated that recombinant soluble-form TM domains exert therapeutic effects in amelioration of various inflammatory disorders, including atherosclerosis, AAA, sepsis, and diabetic nephropathy. 12,[18][19][20][21] Despite well-documented anti-inflammatory properties of soluble-form TM, the function and significance of membranebound TM in inflammatory responses remain largely undetermined. Studies have identified TM expression by monocytes and macrophages.…”

mentioning

confidence: 99%

Membrane-Bound Thrombomodulin Regulates Macrophage Inflammation in Abdominal Aortic Aneurysm

Wang

Shi

et al. 2015

ATVB

Self Cite

View full text Add to dashboard Cite

Objective— Thrombomodulin (TM), a glycoprotein constitutively expressed in the endothelium, is well known for its anticoagulant and anti-inflammatory properties. Paradoxically, we recently found that monocytic membrane-bound TM (ie, endogenous TM expression in monocytes) triggers lipopolysaccharide- and gram-negative bacteria–induced inflammatory responses. However, the significance of membrane-bound TM in chronic sterile vascular inflammation and the development of abdominal aortic aneurysm (AAA) remains undetermined. Approach and Results— Implicating a potential role for membrane-bound TM in AAA, we found that TM signals were predominantly localized to macrophages and vascular smooth muscle cells in human aneurysm specimens. Characterization of the CaCl 2 -induced AAA in mice revealed that during aneurysm development, TM expression was mainly localized in infiltrating macrophages and vascular smooth muscle cells. To investigate the function of membrane-bound TM in vivo, transgenic mice with myeloid- (LysMcre/TM flox/flox ) and vascular smooth muscle cell–specific (SM22-cre tg /TM flox/flox ) TM ablation and their respective wild-type controls (TM flox/flox and SM22-cre tg /TM +/+ ) were generated. In the mouse CaCl 2 -induced AAA model, deficiency of myeloid TM, but not vascular smooth muscle cell TM, inhibited macrophage accumulation, attenuated proinflammatory cytokine and matrix metalloproteinase-9 production, and finally mitigated elastin destruction and aortic dilatation. In vitro TM-deficient monocytes/macrophages, versus TM wild-type counterparts, exhibited attenuation of proinflammatory mediator expression, adhesion to endothelial cells, and generation of reactive oxygen species. Consistently, myeloid TM–deficient hyperlipidemic mice (ApoE −/− /LysMcre/TM flox/flox ) were resistant to AAA formation induced by angiotensin II infusion, along with reduced macrophage infiltration, suppressed matrix metalloproteinase activities, and diminished oxidative stress. Conclusions— Membrane-bound TM in macrophages plays an essential role in the development of AAA by enhancing proinflammatory mediator elaboration, macrophage recruitment, and oxidative stress.

show abstract

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

Cited by 98 publications

References 39 publications

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

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

Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy

Membrane-Bound Thrombomodulin Regulates Macrophage Inflammation in Abdominal Aortic Aneurysm

Contact Info

Product

Resources

About