Inhibition of the interaction of AGE-RAGE prevents hyperglycemia-induced fibrosis of the peritoneal membrane.
The peritoneal membrane of long-term peritoneal dialysis patients is characterized by a loss of ultrafiltration capacity, associated morphologically with submesothelial fibrosis and neoangiogenesis. Exposure to high glucose concentrations in peritoneal dialysate and the resultant advanced glycation end-products (AGE) accumulation have been implicated in the development of these changes, but their exact pathophysiological role is unknown. We examined the effect of the interaction of AGE with one of their receptors (i.e., RAGE) on the function and structure of the peritoneum exposed to high ambient glucose concentrations. Streptozotocin-induced diabetic rats and control rats were treated during 6 wk with either neutralizing monoclonal anti-RAGE antibodies or control antibodies. The expression of RAGE was strongly enhanced in the peritoneal membrane of the diabetic animals. The diabetic peritonea were characterized by an elevated transport of small solutes, lower ultrafiltration rates, a higher vascular density, and an upregulation of endothelial nitric oxide synthase expression. These parameters were unaffected by treatment with anti-RAGE antibodies. In contrast, anti-RAGE but not control antibodies prevented upregulation of TGF-beta, development of submesothelial fibrosis, and fibronectin accumulation in the peritoneum of diabetic animals. In conclusion, binding of AGE to RAGE increases the expression of TGF-beta and contributes to the development of submesothelial fibrosis. Neoangiogenesis and the resultant loss of ultrafiltration capacity are mediated by different pathogenetic pathways.
De Vriese
An S
AS
*Renal Unit, University Hospital, Gent, Belgium; Medical Department M (Diabetes and Endocrinology), the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; and Division of Endocrinology, Department Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
Flyvbjerg
Allan
A
*Renal Unit, University Hospital, Gent, Belgium; Medical Department M (Diabetes and Endocrinology), the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; and Division of Endocrinology, Department Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
Mortier
Siska
S
*Renal Unit, University Hospital, Gent, Belgium; Medical Department M (Diabetes and Endocrinology), the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; and Division of Endocrinology, Department Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
Tilton
Ronald G
RG
*Renal Unit, University Hospital, Gent, Belgium; Medical Department M (Diabetes and Endocrinology), the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; and Division of Endocrinology, Department Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
Lameire
Norbert H
NH
*Renal Unit, University Hospital, Gent, Belgium; Medical Department M (Diabetes and Endocrinology), the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; and Division of Endocrinology, Department Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
D000418:Albumins / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000951:Antigens, Neoplasm; D001692:Biological Transport; D003921:Diabetes Mellitus, Experimental; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis / Q000378:metabolism; D005355:Fibrosis; D005947:Glucose / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006943:Hyperglycemia / Q000473:pathology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D010537:Peritoneum / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D014508:Urea / Q000378:metabolism
D000418:Albumins; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016212:Transforming Growth Factor beta; D014508:Urea; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D005947:Glucose