Fibrinolysis in patients with diabetic nephropathy determined by plasmin-α2 plasmin inhibitor complexes in plasma

Yagame, Mitsunori; Eguchi, Kazuhiko; Suzuki, Daisuke; Machimura, Hideo; Takeda, Hiroshi; Inoue, Wataru; Tanaka, Kurumi; Kaneshige, Hideaki; Nomoto, Yasuo; Sakai, Hideto

doi:10.1016/0891-6632(90)90018-z

Cited by 13 publications

(7 citation statements)

References 6 publications

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“…The latter is particularly important since the degree of mesangial expansion correlates well with glomerular sclerosis, a hallmark of declining renal function (1,2). Several hypotheses concerning the development of DN have been proposed (6)(7)(8)(9); however, the pathogenesis of this disease is not fully understood.…”

mentioning

confidence: 99%

In Situ Hybridization of Interleukin 6 in Diabetic Nephropathy

Suzuki

Miyazaki²,

Naka³

et al. 1995

Diabetes

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144

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Increased mesangial expansion is one of the most characteristic histological changes in diabetic nephropathy (DN). Although the pathogenesis of DN remains unclear, recent studies associate interleukin (IL) 6 with mesangial proliferative glomerulonephritis. To elucidate the expression and localization of IL-6 mRNA in renal tissues of patients with DN, a high-resolution in situ hybridization using digoxigenin-labeled oligonucleotide was performed. Patients were divided into three groups based on light microscopy findings: mild (group 1), moderate (group 2), and severe (group 3) mesangial expansion. The relationship between the expression of IL-6 mRNA and the degree of glomerular mesangial expansion in DN was examined. Individual cells positive for IL-6 mRNA were observed in glomeruli. These cells were mesangial cells, glomerular epithelial cells, and Bowman's capsule. The signal intensity was strongest in tissues from group 2 but was weak in those from groups 1 and 3. Most cells in the area of mesangial proliferation were strongly stained for IL-6 mRNA, and few positive cells were found in the Kimmelstiel-Wilson nodular lesion. In the interstitium, some tubules, particularly atrophic tubules, and some infiltrating cells were positively stained for IL-6 mRNA. The interstitial expression of IL-6 mRNA correlated significantly with the degree of interstitial injury and was remarkable in tissues from groups 2 and 3. We conclude that IL-6 mRNA is expressed by glomerular resident cells and interstitial cells in the renal tissue of patients with DN and that its expression may be associated with mesangial proliferation and may be involved in the tissue injury of DN.

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mentioning

confidence: 99%

In Situ Hybridization of Interleukin 6 in Diabetic Nephropathy

Suzuki

Miyazaki²,

Naka³

et al. 1995

Diabetes

Self Cite

144

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“…Many studies have reported that the levels of the plasmin-α2AP complex in the plasma are elevated in patients with fibrotic diseases, including diabetic nephropathy, systemic sclerosis, liver cirrhosis and rheumatoid arthritis [17][18][19][20]. Additionally, the expression of α2AP is elevated in fibrotic tissue of several fibrotic diseases model mice [10,12].…”

Section: The Expression Of α2ap In Fibrotic Diseasementioning

confidence: 99%

Alpha2-antiplasmin: A New Target for Fibrotic Diseases

Kanno¹

2015

Biochem Anal Biochem

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Fibrotic diseases are characterized by excessive scarring due to excessive production, deposition, and contraction of the extracellular matrix (ECM). However, the detailed mechanism underlying the development of fibrosis was unclear. Recently, it has been reported that alpha2-antiplasmin (α2AP), which is serine protease inhibitors (serpins), is associated with the development of fibrosis. This review considers the physiological and pathological roles of α2AP in the development of fibrosis, and proposes that α2AP may be a new target for fibrotic disease.

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“…α2AP is synthesized in various tissues; has various functions, such as cytokine production, cell growth, and cell differentiation; and regulates angiogenesis, inflammatory response, immune modulation, tissue repair, bone formation, and brain functions [9][10][11][12][13][14][15][16][17][18]. Many studies have reported that the levels of PAP in plasma are elevated in fibrotic diseases which include systemic sclerosis (SSc), diabetic nephropathy, liver cirrhosis, and rheumatoid arthritis [19][20][21][22]. Recently, we showed that the expression of α2AP is elevated in fibrotic tissue [11,[23][24][25], and α2AP induces the transforming growth factor-β (TGF-β) production through adipose triglyceride lipase (ATGL), which has been described as a member of the calcium-independent phospholipase A 2 (iPLA 2 )/nutrin/patatin-like phospholipase domain-contain 2 (PNPLA2) family, and is associated with pro-fibrotic effects, such as cytokine production, myofibroblast differentiation, and ECM production [11,26].…”

Section: Introductionmentioning

confidence: 99%

Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis

et al. 2020

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Background: Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring because of the excessive production, deposition, and contraction of the extracellular matrix (ECM). However, the detailed mechanisms underlying these disorders remain unclear. It was recently reported that α2-antiplasmin (α2AP) is elevated in fibrotic tissue and that it is associated with the development of fibrosis. In the present study, we examined the mechanism underlying the production of α2AP on the development of fibrosis. Methods: To clarify the mechanism underlying the production of α2AP on the development of fibrosis, we focused on high-mobility group box 1 (HMGB1), which is associated with the development of fibrosis. The mouse model of bleomycin-induced fibrosis was used to evaluate the production of α2AP on the development of fibrosis. Results: We found that HMGB1 induced the production of α2AP through receptor for advanced glycation end products (RAGE) in fibroblasts. Next, we showed that macrophage reduction by a macrophage-depleting agent, clodronate, attenuated the progression of fibrosis and the production of α2AP and HMGB1 in the bleomycininduced mice. We also showed that IL-4-stimulated alternatively activated macrophages induced the production of HMGB1, that IL-4-stimulated alternatively activated macrophage conditioned media (CM) induced pro-fibrotic changes and α2AP production, and that the inhibition of HMGB1 and RAGE attenuated these effects in fibroblasts. Furthermore, the blockade of IL-4 signaling by IL-4Rα neutralizing antibodies attenuated the progression of fibrosis and the production of α2AP and HMGB1 in the bleomycin-induced mice.(Continued on next page) Conclusion: These findings suggest that alternatively activated macrophage-derived HMGB1 induced the production of α2AP through RAGE and that these effects are associated with the development of fibrosis. Our findings may provide a clinical strategy for managing fibrotic disorders.

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Fibrinolysis in patients with diabetic nephropathy determined by plasmin-α2 plasmin inhibitor complexes in plasma

Cited by 13 publications

References 6 publications

In Situ Hybridization of Interleukin 6 in Diabetic Nephropathy

In Situ Hybridization of Interleukin 6 in Diabetic Nephropathy

Alpha2-antiplasmin: A New Target for Fibrotic Diseases

Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis

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