Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice

• Published in: Journal of the American Society of Nephrology Vol. 16; no. 6; pp. 1711 - 1722
• Main Authors: CHOW, Fiona Y, NIKOLIC-PATERSON, David J, OZOLS, Elyce, ATKINS, Robert C, TESCH, Gregory H
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.06.2005
• Subjects: Animals; Associated diseases and complications; Biological and medical sciences; Chemotaxis, Leukocyte - immunology; Diabetes Mellitus, Type 2 - complications; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - immunology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Hyperglycemia - etiology; Intercellular Adhesion Molecule-1 - immunology; Kidneys; Macrophage Activation - immunology; Medical sciences; Mice; Models, Animal; Nephrology. Urinary tract diseases; Obesity - complications; Urinary system involvement in other diseases. Miscellaneous; Endocrinopathy; Kidney disease; Type 2 diabetes; Nephrology; Urinary system disease; Intercellular adhesion molecule 1; Pathogenesis; Rodentia; Cell adhesion molecule; Metabolic diseases; Urology; Recruitment; Vertebrata; Mammalia; Mouse; Animal; Complication; Diabetic nephropathy; Macrophage
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2004070612

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% downward arrow) and 8 mo (85% downward arrow). There was also a significant decrease in glomerular (63% downward arrow) and interstitial (83% downward arrow) 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-beta1, collagen IV, and interstitial alpha-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-beta1. Thus, ICAM-1 appears to be a critical promoter of nephropathy in mouse type 2 diabetes by facilitating kidney macrophage recruitment.