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Intercellular Adhesion Molecule-1 Deficiency Is Protective against Nephropathy in Type 2 Diabetic db/db Mice

Fiona Y. Chow^*,, David J. Nikolic-Paterson^*,, Elyce Ozols^*, Robert C. Atkins^*, and Gregory H. Tesch^*,

^* Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

Address correspondence to: Dr. Gregory Tesch. Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: +61-3-9594-3534; Fax: +61-3-9594-6530; E-mail: gtesch{at}hotmail.com

Received for publication July 28, 2004. Accepted for publication March 9, 2005.

Diabetic nephropathy is a leading cause of end-stage renal failure and is a growing concern given the increasing incidence of type 2 diabetes. Diabetic nephropathy is associated with progressive kidney macrophage accumulation and experimental studies suggest that intercellular adhesion molecule (ICAM)-1 facilitates kidney macrophage recruitment during type 1 diabetes. To ascertain the importance of ICAM-1 in promoting type 2 diabetic nephropathy, the development of renal injury in ICAM-1 intact and deficient db/db mice with equivalent hyperglycemia and obesity between ages 2 and 8 mo was examined and compared with results with normal db/+ mice. Increases in albuminuria (11-fold), glomerular leukocytes (10-fold), and interstitial leukocytes (three-fold) consisting of predominantly CD68+ macrophages were identified at 8 mo in diabetic db/db mice compared with nondiabetic db/+ mice. In comparison to db/db mice, ICAM-1-deficient db/db mice had marked reductions in albuminuria at 6 mo (77%) and 8 mo (85%). There was also a significant decrease in glomerular (63%) and interstitial (83%) leukocytes in ICAM-1-deficient db/db mice, which were associated with reduced glomerular hypertrophy and hypercellularity and tubular damage. The development of renal fibrosis (expression of TGF-1, collagen IV, and interstitial -smooth muscle actin) was also strikingly attenuated in the ICAM-1-deficient db/db mice. Additional in vitro studies showed that macrophage activation by high glucose or advanced glycation end products could promote ICAM-1 expression on tubular cells and macrophage production of active TGF-1. Thus, ICAM-1 appears to be a critical promoter of nephropathy in mouse type 2 diabetes by facilitating kidney macrophage recruitment.

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