Two types of alternatively activated macrophages, M-2a induced by IL-4/IL-13 and M-2c by IL-10/TGF-beta, exhibit anti-inflammatory functions in vitro and protect against renal injury in vivo. Since their relative therapeutic efficacy is unclear, we compared the effects of these two macrophage subsets in murine adriamycin nephrosis. Both subsets significantly reduced renal inflammation and renal injury; however, M-2c macrophages more effectively reduced glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria than M-2a macrophages. The M-2c macrophages were also more effective than M-2a in reduction of macrophage and CD4(+) T-cell infiltration in kidney. Moreover, nephrotic mice treated with M-2c had a greater reduction in renal fibrosis than those treated with M-2a. M-2c but not M-2a macrophages induced regulatory T cells (Tregs) from CD4(+)CD25(-) T cells in vitro, and increased Treg numbers in local draining lymph nodes of nephrotic mice. To determine whether the greater protection with M-2c was due to their capability to induce Tregs, the Tregs were depleted by PC61 antibody in nephrotic mice treated with M-2a or M-2c. Treg depletion diminished the superior effects of M-2c compared to M-2a in protection against renal injury, inflammatory infiltrates, and renal fibrosis. Thus, M-2c are more potent than M-2a macrophages in protecting against renal injury due to their ability to induce Tregs.