<p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p> <p>Increased extracellular matrix (ECM) protein deposition
and capillary basement membrane (BM) thickening are
characteristic features of diabetic retinal microangiopathy.
Recent observations in the authors' laboratories suggest
that high glucose in endothelial cells as well as diabetes
causes up-regulation of total fibronectin (FN), as well as
extradomain-B (EDB) containing the spliced variant of FN,
oncofetal FN, in the retina. This splice variant is normally
absent in mature adult tissues and is believed to be involved
in angiogenesis. In this study, the authors have investigated
the role of C-peptide in the production of ECM
proteins and capillary BM thickening in the retina of diabetic
rats. They investigated retinas from poorly controlled
diabetic BB/Wor rats with or without C-peptide treatment
as well as those from age-matched nondiabetic control rats
after 8 months of diabetes. In addition, the authors investigated
retinas from BBDRZ/Wor rats, a model of type 2
diabetes. Following a treatment period of 8 months, retinal
tissues were harvested for gene expression and histological
analyses. In the retinas of diabetic BB/Wor rats, a
significant increase of oncofetal FN was demonstrated compared
to control rats. C-peptide treatment of BB/Wor rats
completely prevented such increase. Furthermore, retinas
from BBDRZ/Wor rats, did not exhibit any such alteration
in oncofetal FN expression. The authors further examined retinal capillary BM thickening using ultrastructural
morphometry. C-peptide treatment was ineffective in preventing
the diabetes-induced increase in capillary BM thickness.
The authors' previous studies of cultured endothelial
cells demonstrated that oncofetal FN synthesis is, at
least in part, mediated via transforming growth factor-<italic>β</italic>
(TGF-<italic>β</italic>) and endothelin-1 (ET-1). Hence, they examined
these two transcripts in the retina of these animals. Diabetes
caused significant increase in mRNA expression of ET-1 and
TGF-<italic>β</italic>, which was not prevented by C-peptide treatment.
Hence it appears that C-peptide is effective in preventing
diabetes-induced oncofetal FN expression and that these effects
are not mediated via ET-1 or TGF-<italic>β</italic>. In conclusion,
these data suggest that C-peptide is involved in regulating
ECM protein composition. Furthermore, normalization of
diabetes-induced oncofetal FN up-regulation may suggest
importance of C-peptide in advanced alterations in diabetic
retinopathy such as angiogenesis.</p>
[]
Exp Diabesity Res. 2004; 5(1):91-96