ABSTRACT
A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteinuria was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies.
Subject(s)
Hypertension/complications , Kidney Failure, Chronic/etiology , Kidney Glomerulus/pathology , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Mitogen/genetics , Angiotensin II/adverse effects , Animals , Chemokine CCL2/metabolism , Collagen Type I/metabolism , Collagen Type IV/metabolism , Cytokines/metabolism , Discoidin Domain Receptors , Disease Models, Animal , Fibrosis , Inflammation , Kidney Failure, Chronic/genetics , Kidney Failure, Chronic/pathology , Lipopolysaccharides/adverse effects , Male , Mice , Mice, Transgenic , Receptor Protein-Tyrosine Kinases/immunology , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Mitogen/immunology , Receptors, Mitogen/metabolism , Shock, Septic/chemically induced , Shock, Septic/genetics , Vasoconstrictor Agents/adverse effectsABSTRACT
PURPOSE OF REVIEW: White adipose tissue is necessary for optimal energy homeostasis and the excessive development of fat mass is clearly associated with the metabolic syndrome. The fact that adipocytes secrete a number of specific factors or 'adipokines' has forced a reassessment of the involvement of adipose tissue in a wide range of physiological and pathophysiological processes. Obesity has recently been described as a 'low-grade' inflammatory condition, a state proposed to represent a common determinator in the genesis of obesity-associated pathologies, i.e. diabetes and atherosclerosis. RECENT FINDINGS: Recent reports of an increase in the number of macrophages that infiltrate the fat mass in obese individuals led to the suggestion that adipose tissue itself is a source and site of inflammation. SUMMARY: This review summarizes recent data on the characterization of the macrophage population in fat tissue. Their origin, fate and activation will be considered. The potential involvement of adipose tissue macrophages in the development of insulin resistance and vascular pathologies, as well as in the control of adipose tissue growth and metabolism, will be examined.
