Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 19, Issue 6, Pages 1177-1189Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2007111179
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Funding
- Intramural NIH HHS [Z01 DK036149] Funding Source: Medline
- NCI NIH HHS [R01 CA069212, R01 CA 069212] Funding Source: Medline
- NIAMS NIH HHS [K01 AR051367, KO1 AR 051367] Funding Source: Medline
- NIDDK NIH HHS [R01 DK056848, DK 36149, R01 DK052369, DK 52369, R01 DK036149, DK 56848] Funding Source: Medline
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Chemokines are instrumental in macrophage- and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas(lpr) mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2(-/-) and wild-type (WT) MRL-Fas(lpr) kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10(-/-) MRL-Fas(lpr) mice, and CXCL10(-/-) C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3(-/-), CXCL9(-/-), and CXCL10(-/-) B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3(-/-) and CXCL9(-/-) mice but not in CXCL10(-/-) mice. With nephrotoxic serum nephritis, CXCR3(-/-) and CXCL9(-/-) mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9 or CXCR3 may be a potential therapeutic target for human immune-mediated kidney diseases.
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