coronary artery sclerosis, myocardial and kidney fibrosis in ZDF
rats
As mentioned above, complications are one of the main causes of death in
patients with diabetes, and whether anti-diabetes drugs can alleviate
these complications has become an important consideration in the
development of such drugs. The main complication of diabetes is
coronary artery sclerosis
(Ikonomidis et al., 2016;
Naito & Miyauchi, 2017). Using H&E and
periodic acid-Schiff staining, we found that the CAG -treated
mice had thinner coronary arteries than the vehicle group (Figure 4A and
4B). The thinning effect on the coronary arteries of CAG was
even stronger than that of Dapagliflozin. This result corresponded to an
increase in the plasma HDL-c/LDL-c ratio in rats treated withCAG (Figure 3I), suggesting that CAG can effectively
reverse coronary atherosclerosis.
Also, epidemiological studies have shown that with the development of
diabetes, multiple tissues collapse, such as myocardial fibrosis and
renal degeneration, which can also lead to cardiovascular complications
and diabetic nephropathy (Pop-Busui et
al., 2017). We then determined the protective effects of CAG on
cardiovascular and nephropathy complications in ZDF rats. By using the
Sirius staining (for collagen) and Masson staining (for fiber), a
significant accumulation of collagen in the heart, which is a pathologic
indicator of myocardium fibrosis, was observed in the vehicle group (as
indicated by the black arrow in Figure 5A), compared with the lean
group. Dapagliflozin and CAG could efficiently decrease
collagen and fiber to a similar level of that in the lean mice (Figure
5A-5C). These ameliorating effects were well coincided with their
effects in reducing myocardial fibrosis in ZDF diabetes rats. These two
compounds have also been shown to relieve fibrosis in the kidney similar
to that in the heart. (Figure 5D-5F). Immunohistochemistry analysis of
TGF-β1 protein, a representative biomarker of fibrosis, further
confirmed the anti-fibrosis effects of CAG in the heart and the
kidney as indicated by a significant decrease in the expression of
TGF-β1 (Figure 5G-5H).