In the present study, the role of endothelin-1 (ET-1) on alterations
of hepatic and renal metallothionein (MT) and trace metals
(Zn, Cu, and Fe) were investigated in streptozotocin (STZ)-
induced diabetic rats. Diabetic rats, age- and sex-matched controls,
as well as control and diabetic animals on a dual ETA/ETB receptor
blocker, bosentan, were investigated after 6 months of follow-up.
MT was measured by cadmium-heme assay. Metals were measured
by atomic absorption spectrometer. ET-1 mRNA was analyzed by
reverse transcriptase–polymerase chain reaction (RT-PCR) technique.
Hepatic and renal ET-1 mRNA was increased in diabetic
rats as compared to control rats, along with an increase in both
hepatic and renal MT proteins. The increased hepatic MT protein
level was associated with decreases in hepatic Cu and Fe, whereas
increased renal MT was associated with increases in renal Cu and
Fe accumulation. Zn levels were unaltered in both organs in diabetic
rats. Bosentan treatment partially prevented the increase in
MT levels in both liver and kidney, along with reduced serum creatinine
and increased urinary creatinine levels. Further bosentan
treatment corrected the increased Cu and Fe levels in the kidney in
diabetic rats, but reduced hepatic Cu and Fe levels. No significant
effects of bosentan treatment on nondiabetic rats were observed.
The data suggest that the possible effects of ET antagonism in diabetes
may be mediated via changes in MT and trace metals.
