Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways

Huh, Kyu Ha; Ahn, Hyung Joon; Park, Jehyun; Ju, Man Ki; Song, Joo Seok; Kim, Myoung Soo; Kim, Soon Il; Kim, Yu Seun

doi:10.1007/s00467-008-1075-8

Cited by 5 publications

(3 citation statements)

References 36 publications

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“…The analysis showed that total ROS was significantly increased in AL compared to healthy controls; in contrast, it was decreased in LN compared to AL. It has been demonstrated that cyclophosphamide can induce [ 36 ], whereas, mycophenolate can inhibit ROS production [ 37 , 38 ] in several cell types. Similarly, MDA a marker of lipid peroxidation was increased in AL compared to healthy controls; on the other hand, it was reduced in LN compared to AL.…”

Section: Discussionmentioning

confidence: 99%

Serum Thiols as a Biomarker of Disease Activity in Lupus Nephritis

et al. 2015

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Lupus Nephritis (LN) develops in more than half of the Systemic Lupus Erythematous (SLE) patients. However, lack of reliable, specific biomarkers for LN hampers clinical management of patients and impedes development of new therapeutics. The goal of this study was to investigate whether oxidative stress biomarkers in patients with SLE is predictive of renal pathology. Serum biochemical and oxidative stress markers were measured in patients with inactive lupus, active lupus with and without nephritis and compared to healthy control group. To assess the predictive performance of biomarkers, Receiver Operating Characteristic (ROC) curves were constructed and cut-offs were used to identify SLE patients with nephritis. We observed an increased oxidative stress response in all SLE patients compared to healthy controls. Among the several biomarkers tested, serum thiols had a significant inverse association with SLE Disease Activity Index (SLEDAI). Interestingly, thiols were able too aptly differentiate between SLE patients with and without renal pathology, and serum thiol levels were not affected by immunosuppressive drug therapy. The decreased thiols in SLE correlated significantly with serum creatinine and serum C3 levels. Further retrospective evaluation using serum creatinine or C3 levels in combination with thiol’s cutoff values from ROC analysis, we could positively predict chronicity of renal pathology in SLE patients. In summary, serum thiols emerge as an inexpensive and reliable indicator of LN, which may not only help in early identification of renal pathology but also aid in the therapeutic management of the disease, in developing countries with resource poor settings.

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Section: Discussionmentioning

confidence: 99%

Serum Thiols as a Biomarker of Disease Activity in Lupus Nephritis

et al. 2015

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“…Oleate has been reported to induce myofibroblast phenotype in mesangial cells through transforming growth factor (TGF)-β1 activation, which suggests that elevated FFAs may induce ECM remodeling and renal fibrosis (13). We have observed previously that oleate-induced ROS upregulate fibronectin (FN) in murine mesangial cells (MMCs) (14). …”

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Catalase Deficiency Accelerates Diabetic Renal Injury Through Peroxisomal Dysfunction

et al. 2012

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Mitochondrial reactive oxygen species (ROS) play an important role in diabetes complications, including diabetic nephropathy (DN). Plasma free fatty acids (FFAs) as well as glucose are increased in diabetes, and peroxisomes and mitochondria participate in FFA oxidation in an interconnected fashion. Therefore, we investigated whether deficiency of catalase, a major peroxisomal antioxidant, accelerates DN through peroxisomal dysfunction and abnormal renal FFA metabolism. Diabetes was induced by multiple injections of low-dose streptozotocin into catalase knock-out (CKO) and wild-type (WT) C57BL/6 mice. Murine mesangial cells (MMCs) transfected with catalase small interfering RNA followed by catalase overexpression were used to further elucidate the role of endogenous catalase. Despite equivalent hyperglycemia, parameters of DN, along with markers of oxidative stress, were more accelerated in diabetic CKO mice than in diabetic WT mice up to 10 weeks of diabetes. CKO mice and MMCs showed impaired peroxisomal/mitochondrial biogenesis and FFA oxidation. Catalase deficiency increased mitochondrial ROS and fibronectin expression in response to FFAs, which were effectively restored by catalase overexpression or N-acetylcysteine. These data provide unprecedented evidence that FFA-induced peroxisomal dysfunction exacerbates DN and that endogenous catalase plays an important role in protecting the kidney from diabetic stress through maintaining peroxisomal and mitochondrial fitness.

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“…These immunosuppressive properties have led to the clinical use of MMF in several forms for treatment of glomerulonephritis and in organ transplantation [17]. In addition, several studies have shown that MMF or MPA may inhibit the production of reactive oxygen species and activation of the mitogen-activated protein kinases such as extracellular signal-regulated kinase 1/2 and p38 kinase in MCs [18,19], decrease the production of lymphocyte-and macrophage-derived cytokines and growth factors, especially TGF-β 1 [20], inhibit ECM deposition [21], and block the proliferation of fibroblasts, vascular smooth muscle and MCs [21]. Furthermore, clinical trials have shown that the combination of MMF and a reduction in the CsA dose may be effective in preventing the progression of chronic allograft nephropathy [22,23].…”

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Effect of Mycophenolic Acid on Cyclosporin A-Induced Fibronectin Expression in Rat Mesangial Cells

Park¹,

Kim²,

et al. 2013

Pharmacology

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This study was undertaken to determine if mycophenolic acid (MPA) inhibits the profibrotic action of cyclosporin A (CsA) and, if so, to determine the molecular mechanisms involved. The effect of MPA treatment on CsA-induced signaling through the transforming growth factor-β (TGF-β)/Smad pathway was evaluated by immunoblot analysis in cultured primary rat mesangial cells. Treatment of cells with 1 µmol/l MPA did not significantly decrease the CsA-induced expression of TGF-β₁, but partially reversed the increases in Smad3 phosphorylation and fibronectin (FBN) production, and increased Smad7 expression. These results suggest that MPA may ameliorate CsA-induced FBN production by modulating the Smad signaling pathway. This study provides evidence that MPA can attenuate CsA-induced renal injury after kidney transplantation.

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Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways

Cited by 5 publications

References 36 publications

Serum Thiols as a Biomarker of Disease Activity in Lupus Nephritis

Serum Thiols as a Biomarker of Disease Activity in Lupus Nephritis

Catalase Deficiency Accelerates Diabetic Renal Injury Through Peroxisomal Dysfunction

Effect of Mycophenolic Acid on Cyclosporin A-Induced Fibronectin Expression in Rat Mesangial Cells

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