Lupus nephritis is a life-threatening complication of systemic lupus erythematosus (SLE). Various growth factors, cytokines, and chemokines are implicated in the development of SLE. However, the pathophysiological processes involved in the development of lupus nephritis still remain unclear. In this study, we examined the involvement of activin A, a member of TGF-β superfamily, in the progression of renal damage in lupus-prone MRL-lpr mice. Activin A was was not expressed in the kidneys of normal C57BL/6 mice but was detectable in perivascular infiltrating CD68-positive cells in the kidneys of MRL-lpr mice. Urinary activin A, which was also absent in normal C57BL/6 mice, was detectable in MRL-lpr mice from 16 weeks onwards. Urinary activin A levels were significantly correlated with the number of perivascular inflammatory cell layers, the number of crescentic glomeruli, and the percentage of EVG-positive fibrotic areas, but not with urinary protein levels or serum activin A. When activin action was blocked in vivo by the intraperitoneal administration of an activin antagonist, follistatin, the number of cresentic glomeruli, percentage of EVG-positive fibrotic areas, CD68-positive cell infiltration, and proteinuria were significantly reduced in a dose-dependent manner. These data suggest that infiltrating macrophage-derived activin A is involved in the progression of renal damage in MRL-lpr mice.