title: CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis.
abstract: 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 (Th1) 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 Cxcl10 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 (Foxn1(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 Cxcl10 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 Th1 lymphocytes, may prime proinflammatory macrophages that consequently aggravate renal injury.
authors.affiliation: Centers for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: D
authors.initials: D
authors.lastname: Petrovic-Djergovic
authors.forename: M
authors.initials: M
authors.lastname: Popovic
authors.forename: S
authors.initials: S
authors.lastname: Chittiprol
authors.forename: H
authors.initials: H
authors.lastname: Cortado
authors.forename: R F
authors.initials: RF
authors.lastname: Ransom
authors.forename: S
authors.initials: S
authors.lastname: Partida-Sánchez
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009401:Nephrosis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011692:Puromycin Aminonucleoside / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D017208:Rats, Wistar; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; D014409:Tumor Necrosis Factor-alpha; D011692:Puromycin Aminonucleoside; D007371:Interferon-gamma
keywords: CXCL10; chemokines; kidney injury; macrophages; nephrotic syndrome