60 The kidneys of mice with autoimmune disease acquire a hypofibrinolytic/procoagulant state that correlates with the development of glomerulonephritis and tissue microthrombosis

Yamamoto, Kōji; Loskutoff, David J.

doi:10.1016/s0268-9499(97)80175-0

Cited by 17 publications

(28 citation statements)

References 6 publications

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“…In any case, it seems likely that both TGF-␤ and TNF-␣ contribute to the increased PAI-1 in this model because the combined pattern of PAI-1 mRNA induction by these cytokines (Fig. 6) resembles the pattern in the kidneys of mice with lupus nephritis (Keeton et al, 1995;Yamamoto and Loskutoff, 1997). The increase in PAI-1 will not only inhibit proteolysis and increase the accumulation of extracellular matrix, but it may also lead to increased local procoagulant potential.…”

Section: Yamamoto and Loskutoffmentioning

confidence: 77%

“…Because both cytokines have been reported to induce PAI-1 gene expression (Sawdey and Loskutoff, 1991;Sawdey et al, 1989), and because PAI-1 was previously correlated to the progression of lupus nephritis in MRL lpr/lpr mice (Keeton et al, 1995;Yamamoto and Loskutoff, 1997), we also examined the ability of these cytokines to induce renal PAI-1. These studies were initiated because increased renal expression of both cytokines frequently correlates with the disease state.…”

Section: Discussionmentioning

confidence: 99%

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Expression of Transforming Growth Factor-β and Tumor Necrosis Factor-α in the Plasma and Tissues of Mice with Lupus Nephritis

Yamamoto

Loskutoff

2000

Laboratory Investigation

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SUMMARY:Although elevated levels of transforming growth factor-␤ (TGF-␤) and tumor necrosis factor-␣ (TNF-␣) have been implicated in renal disease, the tissue distribution and cellular localization of the induced cytokines is not well established. In this study, we investigated the expression of these cytokines during the progression of lupus nephritis in MRL lpr/lpr mice. The concentration of both cytokines increased in the plasma of these animals in an age-dependent manner, and there was an age-dependent induction of TGF-␤ and TNF-␣ mRNAs in their kidneys. Although the increase in TGF-␤ mRNA was specific for the kidney, the increase in TNF-␣ mRNA was widespread and also could be demonstrated in the liver, lung, and heart. In situ hybridization analysis of renal tissues from the lupus-prone mice localized TGF-␤ mRNA to the glomerulus, and more specifically, to resident glomerular cells and inflammatory cells infiltrating periglomerular spaces in the nephritic lesions. The signals for TNF-␣ mRNA were detected only in inflammatory cells and were distributed throughout the nephritic kidney. Plasminogen activator inhibitor-1 (PAI-1) is known to be elevated in the glomeruli of MRL lpr/lpr mice, and intraperitoneal administration of either TGF-␤ or TNF-␣ into normal mice markedly induced the expression of this potent inhibitor of fibrinolysis in renal glomerular or tubular cells in vivo. These results suggest that the increased renal expression of both cytokines may contribute to the development of lupus nephritis in this model and raise the possibility that PAI-1 may be involved. The fact that TGF-␤ is specifically induced in the kidney whereas TNF-␣ increases in a variety of tissues, supports the hypothesis that the renal specificity of this disorder reflects the abnormal expression of TGF-␤. (Lab Invest 2000, 80:1561-1570.L upus nephritis which often accompanies the autoimmune disorder, systemic lupus erythematosus, is characterized by extracellular matrix accumulation and the formation of glomerular, tubular, vascular, and interstitial lesions (Hayslett and Kashgarian, 1993). Inflammatory and immunological processes have been implicated in the development of this nephropathy, including the elaboration of transforming growth factor-␤ (TGF-␤) and tumor necrosis factor-␣ (TNF-␣) (Border and Ruoslahti, 1992;Boswell et al, 1988;Brennan et al, 1989;Moll et al, 1995).TGF-␤ is a multifunctional cytokine that can either inhibit or stimulate cellular proliferation and, as such, seems to play a critical role in tissue repair and regeneration after injury (Border and Ruoslahti, 1992). This cytokine not only stimulates the synthesis of individual matrix components, including fibronectin (Ignotz and Massagu, 1986), collagens (Roberts et al, 1986), and proteoglycans (Bassols and Massagu, 1988;Border et al, 1990a), but it also blocks matrix degradation by decreasing the synthesis of proteases and by increasing the levels of protease inhibitors (Edwards et al, 1987;Laiho et al, 1987). Thus, the expression of TGF-␤ may promote the...

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Section: Yamamoto and Loskutoffmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Expression of Transforming Growth Factor-β and Tumor Necrosis Factor-α in the Plasma and Tissues of Mice with Lupus Nephritis

Yamamoto

Loskutoff

2000

Laboratory Investigation

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“…Fibrin deposits have been reported comprehensively in a wide variety of renal diseases, such as crescentic glomerulonephritis (10), mesangioproliferative glomerulonephritis (11), and murine autoimmune glomerulonephritis (29), and in renal I/R as well (30). Although tPAϪ/Ϫ mice seemed to show more fibrin deposits in the renal interstitial areas compared with WT mice after I/R, there was no statistically significant difference.…”

Section: Discussionmentioning

confidence: 99%

Tissue-Type Plasminogen Activator Modulates Inflammatory Responses and Renal Function in Ischemia Reperfusion Injury

Roelofs¹,

Rouschop²,

Leemans³

et al. 2006

Journal of the American Society of Nephrology

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Acute renal failure is often the result of ischemia-reperfusion (I/R) injury. Neutrophil influx is an important damaging event in I/R. Tissue-type plasminogen activator (tPA) not only is a major fibrinolytic agent but also is involved in inflammatory processes. A distinct upregulation of tPA after I/R, with de novo tPA production by proximal renal tubules, was found. For investigating the role of tPA in I/R, renal ischemia was induced in tPA؊/؊ and wild-type (WT) mice by clamping both renal arteries for 35 min followed by reperfusion. Mice were killed 1, 5, and 10 d after reperfusion. After 1 d, tPA؊/؊ mice displayed significantly less neutrophil influx into the interstitial area compared with WT mice. In addition, tPA؊/؊ mice showed quicker recovery of renal function than WT mice. The protocol was repeated after injection of tPA-antisense oligonucleotides into WT mice, leading to even more explicit results: Antisense-treated mice showed less histologic damage, better renal function, and less neutrophil influx than control mice. Surprising, complement C3 concentration, levels of proinflammatory cytokines and chemokines, intercellular adhesion molecule-1 expression, and matrix metalloproteinase activity were similar in WT and tPA؊/؊ mice. Plasmin activity levels in WT and tPA؊/؊ kidneys were also comparable, indicating that tPA influences neutrophil influx into ischemic renal tissue independent from plasmin generation. This study shows that targeting tPA could be of therapeutic importance in treating I/R injury by diminishing neutrophil influx and preserving renal function.

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“…Several in situ hybridization studies have demonstrated PAI-1 mRNA in diseased glomeruli and tubules and an inflamed interstitium, but counterstaining studies with specific cellular markers have not been performed to clearly establish the specific identity of the PAI-1-transcribing cells. PAI-1 mRNA has been identified in glomerular parietal epithelial cells in several pathological states (11,63,88,105,122,182) and in cells presumed to be mesangial (68,105,122,179), visceral epithelial (36), and glomerular endothelial (62,105,122,132,179). Intrarenal cells thought to be inflammatory leukocytes (38,62,68,88,172,182) and renal tubules (36,38,39,105,122) may also become a source of PAI-1.…”

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confidence: 99%

Plasminogen activator inhibitor-1 and the kidney

Eddy

2002

American Journal of Physiology-Renal Physiology

174

132

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Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that was isolated 20 years ago. First recognized as an inhibitor of intravascular fibrinolysis, it is now evident that PAI-1 is a multifunctional protein with actions that may be dependent on or independent of its protease inhibitory effects. The latter often involve interactions between PAI-1 and vitronectin or the urokinase receptor. The protease-inhibitory actions of PAI-1 extend beyond fibrinolysis and include extracellular matrix turnover and activation of several proenzymes and latent growth factors. PAI-1 has been implicated in several renal pathogenetic processes, including thrombotic microangiopathies and proliferative and/or crescentic glomerulopathies. Most recently, it has become clear that PAI-1 also plays a pivotal role in progressive renal disease, both glomerulosclerosis and tubulointerstitial fibrosis. An active area of present research interest, untold stories are likely to be uncovered soon.

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60 The kidneys of mice with autoimmune disease acquire a hypofibrinolytic/procoagulant state that correlates with the development of glomerulonephritis and tissue microthrombosis

Cited by 17 publications

References 6 publications

Expression of Transforming Growth Factor-β and Tumor Necrosis Factor-α in the Plasma and Tissues of Mice with Lupus Nephritis

Expression of Transforming Growth Factor-β and Tumor Necrosis Factor-α in the Plasma and Tissues of Mice with Lupus Nephritis

Tissue-Type Plasminogen Activator Modulates Inflammatory Responses and Renal Function in Ischemia Reperfusion Injury

Plasminogen activator inhibitor-1 and the kidney

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