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Abstract: PO1405

Effect of Mycophenolate and Rapamycin on Pro-Inflammatory and Pro-Fibrotic Mediators in Human Mesangial Cells

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Zhang, Chenzhu, Department of Medicine, The University of Hong Kong, Hong Kong, China
  • Yung, Susan, Department of Medicine, The University of Hong Kong, Hong Kong, China
  • Chan, Tak Mao Daniel, Department of Medicine, The University of Hong Kong, Hong Kong, China
Background

A significant proportion of lupus nephritis (LN) patients develop chronic kidney disease. TGF-β1 expression is increased in renal biopsies from LN patients and it plays an important role in kidney fibrosis. We previously reported that mycophenolate and rapamycin inhibited pro-fibrotic processes in resident kidney cells in murine LN. We proceeded to investigate the effect of mycophenolate and rapamycin on inflammatory and fibrotic processes in human mesangial cells.

Methods

Growth-arrested human mesangial cells (HMC) were incubated with or without exogenous TGF-β1 (10 ng/ml), in the presence or absence of mycophenolic acid (1 μg/ml) or rapamycin (3 ng/ml), for up to 72 h. The effect on inflammatory and fibrotic processes was examined.

Results

TGF-β1 increased IL-6 and MCP-1 secretion, and α-smooth muscle actin, collagen and fibronectin expression, in a time-dependent manner, accompanied by increased ERK, mTOR and PI3K phosphorylation (P<0.05, for all). Constitutive IL-6 and MCP-1 secretion was mediated through PI3K phosphorylation, whereas IL-6 and MCP-1 secretion induced by TGF-β1 was mediated through PI3K, mTOR and ERK phosphorylation. Cell activation was mediated through PI3K and mTOR activation, while increased collagen and fibronectin expression was mediated through ERK, PI3K and mTOR. Mycophenolic acid inhibited the secretion of pro-fibrotic and pro-inflammatory cytokines, cell activation, and collagen and fibronectin expression, through suppressing ERK activation. Rapamycin inhibited similar processes through suppression of mTOR and ERK activation. Overall, the inhibitory actions of mycophenolic acid were comparable to that of rapamycin.

Conclusion

Mycophenolate and rapamycin both suppress pro-inflammatory and pro-fibrotic processes in mesangial cells by targeting signaling pathways that overlap partially.

Funding

  • Government Support – Non-U.S.