Novel therapeutic targets for diabetic nephropathy.

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Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. To find a novel therapeutic target for diabetic nephropathy, we induced diabetes or 5/6 nepphrectomy in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice and examined the renal pathology over a period of 6 months. The infiltration of macrophages, albuminuria anc renal tissue injuries were markedly suppressed in diabetic ICAM-1(-/-) mice or 5/6 nephrectomized ICAM-1(-/-) mice compared with ICAM-1(+/+) mice. We investigated the gene expression profiles in the kidneys of these mice using DNA microarray system. Several genes including osteopontin, cholecystokinin (CCK) and scavenger receptor A are up-regulated in the kidneys of diabetic or 5/6 nephretomized ICAM-1(+/+) mice, while the expression levels of these genes were decreased in diabetic or 5/6 nephrectomized ICAM-1(-/-) mice as compared to ICAM-1(+/+) mice. Scavenger receptor A deficient mice revealed diminished albuminuria and renal injuries after induction of dianetes as compared with wild type mice. Renal injuries were ameliorated in CCK-receptor deficient mice after 5/6 nephrectomy as compared with wild type mice. Our results indicate that microinflammation is involved in the pathogenesis of diabetic nephropathy. CCK, scavenger receptor A and osteopontin may be novel therapeutic target for diabetic nephropathy.