Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney

Badid, Chérif; Vincent, Madeleine; McGregor, Brigitte; Melin, Martine; Hadj‐Aïssa, Aoumeur; Veysseyre, C.N.; Hartmann, Daniel; Desmoulière, Alexis; Laville, Maurice

doi:10.1046/j.1523-1755.2000.00140.x

Cited by 145 publications

(113 citation statements)

References 26 publications

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“…Whilst vimentin is not specific for fibroblastoid cells [72], staining of both vimentin and tubular β-catenin is currently being used clinically to assess early renal injury (clinical trial NCT#01079143) [73]. Although α-SMA represents the most commonly used marker in EMT, heterogeneity of expression means that this protein is not a definitive marker [74], and clarification of EMT in fibrosis should be regarded with caution, since confirmation of this phenotypic transformation appears to depend upon a complex interplay of events. The concept that cells of an epithelial origin are able to undergo a phenotypic transformation in response to pathophysiological stimuli and ultimately traverse the TBM has, up until recently, been universally accepted.…”

Section: Emt In the Kidneymentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

171

187

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Transforming Growth Factor-beta (TGF-β) is a pro-sclerotic cytokine widely associated with the development of fibrosis in diabetic nephropathy. Central to the underlying pathology of tubulointerstitial fibrosis is epithelial-to-mesenchymal transition (EMT), or the trans-differentiation of tubular epithelial cells into myofibroblasts. This process is accompanied by a number of key morphological and phenotypic changes culminating in detachment of cells from the tubular basement membrane and migration into the interstitium. Ultimately these cells reside as activated myofibroblasts and further exacerbate the state of fibrosis. A large body of evidence supports a role for TGF-β and downstream Smad signaling in the development and progression of renal fibrosis. Here we discuss a role for TGF-β as the principle effector in the development of renal fibrosis in diabetic nephropathy, focusing on the role of the TGF-β1 isoform and its downstream signaling intermediates, the Smad proteins. Specifically we review evidence for TGF-β1 induced EMT in both the proximal and distal regions of the nephron and describe potential therapeutic strategies that may target TGF-β1 activity.

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Section: Emt In the Kidneymentioning

confidence: 99%

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Hills

Squires

2011

Cytokine & Growth Factor Reviews

171

187

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“…In addition, MMF appears to have a variety of anti-inflammatory actions that are independent of its effect on cell-mediated immunity. [7][8][9][10][11] Despite the successful induction of proliferative GN, relapses are common, ranging from 10 to 65%. [12,13] Continued renal damage can adversely affect long-term renal survival with each relapse, [14] and the treatment of these relapses is burdened by the toxicity.…”

Section: G M Sahin Et Almentioning

confidence: 99%

Mycophenolate Mofetil versus Azathioprine in the Maintenance Therapy of Lupus Nephritis

Şahin

Kızıltaş

et al. 2008

Renal Failure

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Background. Renal involvement is one of the major determinants of the outcome in patients with systemic lupus erythematosus. Renal involvement contributes to both morbidity and mortality of the patients as well as indirectly through side effects of therapy directed at the renal lesions. The aim of the study was to evaluate the efficacy of mycophenolate mofetil (MMF) and azathioprine (AZA) in the maintenance therapy of lupus nephritis. Methods. Thirty-two patients from our center with diagnosed lupus nephritis World Health Organization Class III, IV, V were treated with IVC (0.75-1g/month) for six months in addition to steroid therapy, and then with AZA (n = 15) or MMF (n = 17) as a maintenance therapy. The efficacy of two drugs was compared with changes in serum creatinine, creatinine clearance, 24 hour urine protein excretion, cholesterol, anti-dsDNA antibody, and urine sediment. Results. Mean follow-up time was 41.5 + 7 months. The total remission occurred in 84% of patients (82% with MMF and 87% with AZA), with a complete remission rate of 59.3% (58% with MMF and 60% with AZA) and a partial remission rate of 25% (22% with MMF and 27% with AZA). The urinary protein excretion before MMF treatment was 1.9 + 1 g/dL and decreased significantly to 0.91 + 0.6 g/dL (p = 0.028) after treatment, and decreased from 1.58 + 0.7g/dL to 0.4 + 0.23g/dL in the AZA group (p = 0.04). The serum creatinine level decreased from 1.32 + 0.7 mg/dL to 1.12 + 0.68 mg/dL in the MMF group (p = 0.23), and decreased from 0.91 + 0.23mg/dL to 0.88 + 0.23 mg/dL in the AZA group (p = 0.49). There was no significant change between two groups (p = 0.1). The serum cholesterol decreased from 229 + 57 mg/dL to 171 + 9 mg/dL (p = 0.002), and serum triglyceride level decreased from 228 + 116 mg/dL to 98 + 35 mg/dL (p = 0.004) in the MMF treatment, but no significant change was seen in AZA group. There was no significant difference between the two groups considering the rates of doubling of serum creatinine, progression to end-stage renal failure, relapses, and documented side effects, as well. Conclusion. Both therapeutic approaches with MMF or AZA, in combination with corticosteroids, are effective as a maintenance therapy for lupus nephritis.

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“…4 Its renoprotective action was related to reduced infiltration of inflammatory cells, but direct effects on resident cells, mainly interstitial myofibroblasts and mesangial cells, have also been suggested. 5,6 We and others have demonstrated that MPA inhibits mesangial proliferation and secretion of extracellular matrix proteins, 7,8 all effects that might contribute to the favorable effects of mycophenolate mofetil in chronic fibrotic kidney diseases. However, inhibition of mesangial activation caused by MPA treatment was accompanied by a strong and sustained increase in SMA expression, 8 which is usually associated with mesangial proliferation.…”

mentioning

confidence: 98%

Cytoskeletal Reorganization by Mycophenolic Acid Alters Mesangial Cell Migration and Contractility

et al. 2003

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Abstract-Cytoskeleton alterations are a hallmark of mesangial cell activation during glomerulosclerosis. The aim of this study was to investigate whether mycophenolic acid (MPA) affects cytoskeletal organization and motility of human mesangial cells. Using the IP15 cell line, we found that treatment with 1 mol/L MPA inhibited both receptor-dependent (angiotensin II) and receptor-independent (KCl) contractile responses, as well as serum-induced migration activity, suggesting alterations in the intracellular mechanisms that control mesangial cell motility. Immunofluorescence studies of MPA-treated cells provided evidence for decreased membrane disassembly/reassembly of ␣-smooth muscle actin and F-actin fibers, which was correlated with sustained quantitative and qualitative modifications of actin-associated proteins: calponin was overexpressed and became associated with actin fibers, whereas phosphorylation levels of cofilin and myosin light chain increased, suggesting both an activation of the mechanisms responsible for actin polymerization and an inhibition of actin-depolymerizing processes. These observations support a stabilizing effect of MPA on the mesangial actin cytoskeleton, which constitutes an additive action by which MPA, beyond its anti-inflammatory, antiproliferative and antifibrotic properties, might protect against excessive mesangial activation in the context of various glomerulopathies and kidney transplantation.

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Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney

Cited by 145 publications

References 26 publications

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

The role of TGF-β and epithelial-to mesenchymal transition in diabetic nephropathy

Mycophenolate Mofetil versus Azathioprine in the Maintenance Therapy of Lupus Nephritis

Cytoskeletal Reorganization by Mycophenolic Acid Alters Mesangial Cell Migration and Contractility

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