The up-regulation of angiotensin II receptor type 1 and connective tissue growth factor are involved in high-glucose-induced fibronectin production by cultured human dermal fibroblasts.

BACKGROUND: The expansion of extracellular matrix in diabetes occur in many tissues, including skin, but the underlying mechanisms are poorly understood. We were interested to study whether the activation of angiotensin II/receptor type 1 pathway with the consequent involvement of CTGF may be the possible cause of high-glucose-induced matrix abnormalities in cultured dermal fibroblasts.
OBJECTIVE: We aimed to investigate the effect of high glucose on the generation of angiotensin II and the expression of angiotensin II receptors, and on the expression of CTGF mediating the fibronectin production in cultured human dermal fibroblasts.
METHODS: Cell culturing, ELISA, semi-quantitative RT-PCR, Western blotting.
RESULTS: High glucose treatment of cultured dermal fibroblasts led to: (1) the angiotensin II receptor type 1 was up-regulated at the level of mRNA and protein, unlike the receptor type 2; (2) the generation of angiotensin II and the mRNA expression of all components of the local renin-angiotensin system were not altered; (3) the mRNA and protein expression of CTGF was up-regulated, and this effect was cancelled by losartan; (4) the fibronectin production was increased, also was cancelled by losartan, while an anti-CTGF-neutralizing antibody only partly reduced it; (5) TGFbeta1 expression, the secretion of total and active TGFbeta1 were not changed; (6) the hyperosmotic action of high glucose had no effect.
CONCLUSION: The up-regulation of angiotensin II receptor type 1 and the consequent increase of CTGF expression, independently of TGFbeta1, participate in high-glucose-induced fibronectin production in cultured human dermal fibroblasts.