Reversing CXCL10 Deficiency Ameliorates Kidney Disease in Diabetic Mice.

The excessive accumulation of extracellular matrix material in the kidney is a histopathological hallmark of diabetic kidney disease that correlates closely with declining function. Although considerable research has focused on the role of profibrotic factors, comparatively little attention has been paid to the possibility that a diminution in endogenous anti-fibrotic factors may also contribute. Among the latter, the ELR CXC chemokines, CXCL9, 10, and 11, have been shown to provide a 'stop' signal to prevent excessive fibrosis. Although the plasma concentrations of CXCL9 and 11 were similar, those of CXCL10 were markedly lower in diabetic db/db mice when compared with control db/m mice. In cell culture, CXCL10 inhibited kidney fibroblast collagen production in response to high glucose and the prosclerotic growth factor, transforming growth factor-ß. In vivo, rmCXCL10 reduced mesangial and peritubular matrix expansion, albuminuria, and glomerular hypertrophy in db/db mice. In bone marrow, a major source of circulating chemokines, the concentration of CXCL10 was lower in cells derived from diabetic mice compared with their non-diabetic counterparts. Silencing of CXCR3, the cognate receptor for CXCL10, abrogated the anti-fibrotic effects of bone marrow-derived secretions. In conclusion, experimental diabetes is a state of CXCL10 deficiency and that restoration of CXCL10 abundance prevented fibrosis and the development of diabetic kidney disease in mice.