The mechanism responsible for trafficking of monocyte-derived macrophages into kidney in the puromycin aminonucleoside model of nephrotic syndrome in rats (PAN-NS), and the significance of this infiltration, remain largely unknown. CXCL10, a chemokine secreted in many Th1-type inflammatory diseases, exhibits important roles in trafficking of monocytes and activated T-cells. We hypothesized that induction of circulating IFN-γ and glomerular TNF-α during PAN-NS would stimulate release of CXCL10 by podocytes, leading to infiltration of activated immune cells and greater glomerular injury. We found that serum IFN-γ, glomerular Cxcl10 mRNA, and intra- and peri-glomerular macrophage infiltration were strongly induced during the late acute phase of PAN-NS in Wistar rats, but not in nude (Foxn1rnu/rnu) rats lacking functional effector T-lymphocytes. Wistar rats also developed significantly greater proteinuria than nude rats, which could be abolished by macrophage depletion. Stimulation of cultured podocytes with both IFN-γ and TNF-α markedly induced the expression of Cxcl10 mRNA and CXCL10 secretion. Together, these data support our hypothesis that increased circulating IFN-γ and glomerular TNF-α synergistically induce the production and secretion of CXCL10 by podocytes, attracting activated macrophages into kidney tissue. The study also suggests that IFN-γ, secreted from Th1 lymphocytes, may prime pro-inflammatory macrophages that consequently aggravate renal injury.