Transforming Growth Factor-β1 Production Is Correlated With Genetically Determined ACE Expression in Congenic Rats: A Possible Link Between ACE Genotype and Diabetic Nephropathy

摘要

Genetic background appears to modulate the development of diabetic vascular complications. In particular, polymorphisms in the ACE gene have been associated with diabetic nephropathy and, in some studies, macro-vascular complications. However, the links between ACE gene polymorphism and factors implicated in diabetes complications remain unknown. The aim of this study was to determine whether the ACE genotype could modify factors, such as transforming growth factor (TGF)-β1, involved in the complications of diabetes. For this purpose, congenic rats (L.BNAce10), differing from the LOU strain in only a small segment of chromosome 10 containing the ACE locus, were generated. These congenic rats have plasma ACE levels twice as Ugh as the donor strain. Diabetes was induced in rats of both strains, and its effects on ACE and TGF-β1 expressions were evaluated in lungs and kidneys. In lung, the main source of ACE production, ACE mRNA levels and activity were higher in L.BNAce10 rats than in LOU rats. Diabetes increased ACE lung expression in rats of both strains ia a similar manner. TGF-β1 expression was also higher in lungs of L.BNAce10 compared with LOU rats and was also increased by diabetes. Furthermore, a strong correlation was found between TGF-β1 and ACE expressions. In renal arterioles, ACE and TGF-βmRNA expressions were higher in L.BNAce10 rats than LOU rats (both diabetic and nondiabetic). In these vessels, there was also a correlation between ACE and TGF-β1 expressions. Urine TGF-β1 concentration depended on the genotype and was further increased by diabetes. These results show that TGF-β1 expression is correlated with ACE expression and suggest that this growth factor could be a link between ACE gene polymorphism and diabetic vascular complications.