Mycophenolic acid inhibits mesangial cell activation through p38 MAPK inhibition

Ha, Hunjoo; Kim, Myoung Soo; Park, Jehyun; Huh, Joo Young; Huh, Kyu Ha; Ahn, Hyung Joon; Kim, Yu Seun

doi:10.1016/j.lfs.2006.05.001

Cited by 26 publications

(21 citation statements)

References 42 publications

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“…Inhibition of p38 MAPK activation by MPA leads to inhibition of proliferation and ECM synthesis in mesangial cells (Ha et al, 2006). However, inhibition of the activation of p38 MAPK by MPA on has not been reported in renal fibroblasts.…”

Section: Figurementioning

confidence: 98%

“…ICAM-1 and the secretion of CCL2 involves several different cell types. On the other hand, in our in vitro model, we specifically observed that, although TNF-a induced the expression of ICAM-1 and CCL2 in renal fibroblasts, MPA selectively inhibited CCL2 secretion, rather than ICAM-1 expression, in these cells.In cultured mesangial cells, MPA effectively blocked p38 MAPK activation and exogenous guanosine partially reversed this inhibition (Ha et al, 2006). Inhibition of p38 MAPK activation by MPA leads to inhibition of proliferation and ECM synthesis in mesangial cells (Ha et al, 2006).…”

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confidence: 99%

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In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor‐α

Chang

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSERenal fibroblasts play a pivotal role in the development of tubulointerstitial fibrosis, a condition highly predictive of progression towards end-stage renal disease. The present study investigated the anti-mitogenic and anti-inflammatory effects of an inhibitor of inosine monophosphate dehydrogenase, mycophenolic acid (MPA) and the mechanisms underlying its action in normal rat kidney fibroblasts (49F cells). EXPERIMENTAL APPROACHProliferation of 49F cells was studied by tetrazole 3-(4, 5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide (MTT) test, bromodeoxyuridine incorporation and flow cytometry. The cyclins, tumour suppressor genes and phospho-mitogen-activated protein kinases (MAPKs) were semiquantified by immunoblotting. Apoptosis was measured by quantifying the fragmented DNA and the activity of caspase 3. The monocyte chemokine CCL2 was measured by ELISA. The mRNA expression of CCL2 was measured by real-time PCR. KEY RESULTSMycophenolic acid dose-dependently inhibited steady-state proliferation of 49F cells by up-regulation of p21, p27 and p53, in association with a decrease in cyclins D2 and E. Treatment with MPA also triggered apoptosis of 49F cells by activating the caspase 3 cascade. Furthermore, MPA attenuated tumour necrosis factor-a-induced CCL2 expression through down-regulation of p38 MAPK, but not that of ERK1/2 or JNK. CONCLUSIONS AND IMPLICATIONSThe anti-mitogenic and anti-inflammatory effects of MPA were mediated by up-regulation of cell cycle inhibitors and pro-apoptotic signals, and by suppression of p38 MAPK pathway respectively. This dual effect of MPA may form the rationale for animal or clinical trials for the treatment of fibrotic renal diseases. AbbreviationsBrdU, bromodeoxyuridine; ECM, extracellular matrix; IMPDH, inhibitor of inosine monophosphate dehydrogenase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; CCL2; MMF, mycophenolate mofetil; MPA, mycophenolic acid; MTT, tetrazole 3-(4, 5-dimethylthiazol-2-yl-)-2,5-diphenyltetrazolium bromide; TNF-a, tumour necrosis factor-a; VCAM-1, vascular cell adhesion molecule-1 BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2010) IntroductionFibrotic renal disease is characterized by accumulation of extracellular matrix (ECM) proteins within the glomerulus and the interstitium, leading ultimately to glomerulosclerosis and tubulointerstitial fibrosis (Qian et al., 2008;Ma and Fogo, 2007;Qi et al., 2006;Zoja et al., 2006). Glomerulosclerosis is a process by which normal glomerular structure is replaced by accumulated deposits of ECM. It represents a common pathway for the loss of functioning glomeruli associated with most forms of chronic kidney disease (Gagliardini and Benigni, 2007). By contrast, the mechanisms leading to the development of tubulointerstitial fibrosis include transdifferentiation of tubular cells to myofibroblasts, infiltration of monocytes and overproduction of ECM proteins by intrinsic parench...

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Section: Figurementioning

confidence: 98%

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confidence: 99%

In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor‐α

Chang

et al. 2010

British J Pharmacology

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“…Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase 2 (IMPDH2), inhibits not only the proliferation of lymphocytes, but also that of other mesenchymal cells [24][25][26][27][28][29]. We previously reported that MPA inhibited VSMC and MC proliferation and ECM synthesis [27,29,30].…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported that MPA inhibited VSMC and MC proliferation and ECM synthesis [27,29,30]. However, IMPDH2 is only partly involved in the inhibitory action of MPA on mesenchymal cells [31].…”

Section: Introductionmentioning

confidence: 99%

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

Huh

Ahn

Park³

et al. 2009

Pediatr Nephrol

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The synthesis of extracellular matrix (ECM) in mesangial cells (MCs) plays important roles in the development and progression of renal diseases, including chronic allograft nephropathy. Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase 2 (IMPDH2), suppresses MC proliferation and ECM synthesis. However, the exact inhibitory mechanism of MPA on MCs has not been clearly elucidated. In this study we compared the inhibitory effects of MPA and IMPDH2 reduction [by using small interfering RNA (siRNA)] on oleic acid (OA)-induced fibronectin secretion and cellular reactive oxygen species (ROS) in mouse MCs. Growth-arrested MCs were stimulated with OA in the presence or absence of MPA, IMPDH2 siRNA, N-acetylcysteine (NAC), transforming growth factor beta (TGF-beta) antibody or exogenous guanosine. Fibronectin secretion into the medium was examined by Western blot, dichlorodihydrofluorescein (DCF)-sensitive cellular ROS by fluorescence-activated cell scanning (FACS), TGF-beta levels in the media by enzyme-linked immunosorbent assay (ELISA). OA increased fibronectin secretion, TGF-beta and cellular ROS levels. A TGF-beta neutralizing antibody effectively suppressed OA-induced fibronectin secretion. NAC and MPA completely suppressed OA-induced fibronectin secretion and decreased the levels of TGF-beta and cellular ROS. However, IMPDH2 siRNA partly inhibited OA-induced MC activation. Exogenous guanosine successfully reversed the inhibitory effects of IMPDH2 siRNA on OA-induced MC activation. Pleiotropic inhibitory effect of MPA on OA-induced mouse MC activation was mediated via its antioxidant effect on cellular ROS production and partly via inhibition of IMPDH2 itself. Our results implicate ROS as an alternative therapeutic target for the prevention of hyperlipidemia-related glomerulopathy, chronic allograft nephropathy, and subsequent graft loss.

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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 mesangial cell activation through p38 MAPK inhibition

Cited by 26 publications

References 42 publications

In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor‐α

In rat renal fibroblasts, mycophenolic acid inhibits proliferation and production of the chemokine CCL2, stimulated by tumour necrosis factor‐α

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

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

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