CXCL10 induces the recruitment of monocyte‐derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis

Summary 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 T helper type 1 ( T h1) inflammatory diseases, exhibits important roles in trafficking of monocytes and activated T cells. We hypothesized that induction of circulating interferon ( IFN )‐γ and glomerular tumour necrosis factor ( TNF )‐α during PAN‐NS would stimulate the release of CXCL10 by podocytes, leading to infiltration of activated immune cells and greater glomerular injury. We found that serum IFN ‐γ, glomerular C xcl10   mRNA and intra‐ and peri‐glomerular macrophage infiltration were induced strongly during the late acute phase of PAN‐NS in Wistar rats, but not in nude ( F oxn1 rnu/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 C xcl10   mRNA and CXCL10 secretion. Together, these data support our hypothesis that increased circulating IFN ‐γ and glomerular TNF ‐α induce synergistically the production and secretion of CXCL10 by podocytes, attracting activated macrophages into kidney tissue. The study also suggests that IFN ‐γ, secreted from T h1 lymphocytes, may prime proinflammatory macrophages that consequently aggravate renal injury.