Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats

Romero, Freddy; Rodríguez‐Iturbe, Bernardo; Parra, Gustavo; González, Luisandra; Herrera-Acosta, Jaime; Tapia, Edilia

doi:10.1046/j.1523-1755.1999.055003945.x

Cited by 186 publications

(164 citation statements)

References 23 publications

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“…It is interesting that IL-10 was associated with an approximately 50% reduction in this inflammatory response. The possibility that this could be one of the renoprotective mechanisms for IL-10 in this model is supported by a similar study in which treatment of the remnant kidney model with mycophenolate mofetil also reduced macrophage and T cell infiltration with functional and histologic improvement (16).…”

Section: Discussionmentioning

confidence: 63%

IL-10 Suppresses Chemokines, Inflammation, and Fibrosis in a Model of Chronic Renal Disease

Mu¹,

Ouyang²,

Agarwal

et al. 2005

Journal of the American Society of Nephrology

143

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IL-10 is a pluripotent cytokine that plays a pivotal role in the regulation of immune and inflammatory responses. Whereas short-term administration of IL-10 has shown benefit in acute glomerulonephritis, no studies have addressed the potential benefits of IL-10 in chronic renal disease. Chronically elevated blood levels of IL-10 in rats were achieved by administration of a recombinant adeno-associated virus serotype 1 IL-10 (rAAV1-IL-10) vector. Control rats were given a similar dose of rAAV1-GFP. Four weeks after injection, IL-10 levels in serum were measured by ELISA, and chronic renal disease was induced by a 5/6 nephrectomy (n ‫؍‬ 6 in each group). Eight weeks later, rats were killed and renal tissue was obtained for RNA, protein, and immunohistochemical analysis. Serum levels of IL-10 were 12-fold greater in the rAAV1-IL-10 group by 4 wk after rAAV1-IL-10 administration (345 ؎ 169 versus 28 ؎ 15 pg/ml; P ‫؍‬ 0.001), and levels were maintained throughout the experiment. rAAV1-IL-10 treatment resulted in less proteinuria (P < 0.05), lower serum creatinine (P < 0.05), and higher creatinine clearances (P < 0.01) compared with rAAV1-GFP-treated rats.

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Section: Discussionmentioning

confidence: 63%

IL-10 Suppresses Chemokines, Inflammation, and Fibrosis in a Model of Chronic Renal Disease

Mu¹,

Ouyang²,

Agarwal

et al. 2005

Journal of the American Society of Nephrology

143

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“…The MSC-treated animals showed less fibrosis, but they had a reduced glomerulosclerosis index. These partially improved outcomes were also seen following other therapeutic strategies, such as MMF therapy, using the remnant model, where glomerular and interstitial injuries were attenuated despite persistent proteinuria [13,41]. Interestingly, anemia was also reduced in MSC-treated animals.…”

Section: Discussionmentioning

confidence: 67%

“…This drug can ameliorate renal dysfunction and proteinuria associated with fewer areas of segmental sclerosis and interstitial fibrosis, by and reducing ED-1 À , CD43 À , CD18 À , and CD11b þ infiltrating cells [11,12]. However, glomerular hypertrophy and systemic hypertension remained unchanged [13]. Thus, more robust therapies are necessary to halt CDK progression.…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

et al. 2009

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Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury, but their role in chronic kidney diseases is still unknown. More specifically, it is not known whether MSCs halt fibrosis. The purpose of this work was to investigate the role of MSCs in fibrogenesis using a model of chronic renal failure. MSCs were obtained from the tibias and femurs of male Wistar-EPM rats. Female Wistar rats were subjected to the remnant model, and 2|3|10 5 MSCs were intravenously administrated to each rat every other week for 8 weeks or only once and followed for 12 weeks. SRY gene expression was observed in female rats treated with male MSCs, and immune localization of CD73 1 CD90 1 cells at 8 weeks was also assessed. Serum and urine analyses showed an amelioration of functional parameters in MSC-treated animals at 8 weeks, but not at 12 weeks. Masson's trichrome and Sirius red staining demonstrated reduced levels of fibrosis in MSC-treated animals. These results were corroborated by reduced vimentin, type I collagen, transforming growth factor b, fibroblast specific protein 1 (FSP-1), monocyte chemoattractant protein 1, and Smad3 mRNA expression and a smooth muscle actin and FSP-1 protein expression. Renal interleukin (IL)-6 and tumor necrosis factor a mRNA expression levels were significantly decreased after MSC treatment, whereas IL-4 and IL-10 expression levels were increased. All serum cytokine expression levels were decreased in MSC-treated animals. Taken together, these results suggested that MSC therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal injury. The immunosuppressive and remodeling properties of MSCs may be involved in the decreased fibrosis in the kidney.

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“…Indeed, different groups showed that MPA reduces the extent of interstitial fibrosis and glomerular sclerosis also in the 5/6-nephrectomy model, a non-immune-mediated model of progressive renal damage. 22,[33][34][35] To investigate the possible biologic mechanisms underlying the clinical action of this immunosuppressive drug, we decided to apply an exploratory genomic analysis performed as an hypothesis-generating approach. The transcriptomic screening has been extensively used in transplantation to identify biomarkers for an early diagnosis of acute 36 and chronic rejection, 37 but presently, little is known about the change in the genomic profile induced by pharmacologic intervention in transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

Dell'Oglio

Zaza

Rossini

et al. 2010

Journal of the American Society of Nephrology

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Mycophenolic acid (MPA) appears to have anti-fibrotic effects, but the molecular mechanisms underlying this are unknown. We prospectively studied 35 stable kidney transplant recipients maintained on cyclosporine and azathioprine. We converted 20 patients from azathioprine to enteric-coated mycophenolate sodium (EC-MPS) and continued the remaining 15 patients on azathioprine. Exploratory mRNA expression profiling, performed on five randomly selected EC-MPS patients, revealed significant upregulation of neutral endopeptidase (NEP), which is an enzyme that degrades angiotensin II. We confirmed these microarray data by measuring levels of NEP expression in all subjects; in addition, we found that NEP gene expression correlated inversely with proteinuria. In an additional 33 patients, glomerular and tubular NEP protein levels from renal graft biopsies were significantly higher among the 13 patients receiving cyclosporine ϩ EC-MPS than among the 12 patients receiving cyclosporine ϩ azathioprine or 8 patients receiving cyclosporine alone. Glomerular NEP expression inversely correlated with glomerulosclerosis and proteinuria, and tubular NEP expression inversely correlated with interstitial fibrosis. Incubation of human proximal tubular cells with MPA increased NEP gene expression in a doseand time-dependent manner. Moreover, MPA reduced angiotensin II-induced expression of the profibrotic factor plasminogen activator inhibitor-1, and a specific NEP inhibitor completely reversed this effect. Taken together, our data suggest that MPA directly induces expression of neutral endopeptidase, which may reduce proteinuria and slow the progression of renal damage in kidney transplant recipients. 21: 215721: -216821: , 201021: . doi: 10.1681 Over the last decade, the continuous progress in the development of immunosuppressive agents has enhanced both the efficacy and safety of antirejection regimens after renal transplantation, leading to a dramatic reduction in the incidence of acute rejection. 1 This significant improvement in short-term graft outcome was not followed by a similar advance in preventing graft loss caused by chronic graft injury. 2,3 The addition of mycophenolic acid (MPA) into contemporary immunosuppressive regimens represented an important step forward in the development of new therapeutic protocols in kidney transplantation. J Am Soc NephrolMPA exerts its immunosuppressive effect by inhibiting the inosine 5Ј monophosphate dehydro-

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Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats

Cited by 186 publications

References 23 publications

IL-10 Suppresses Chemokines, Inflammation, and Fibrosis in a Model of Chronic Renal Disease

IL-10 Suppresses Chemokines, Inflammation, and Fibrosis in a Model of Chronic Renal Disease

Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

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