One of the major concerns of current diabetes treatment is the maintenance of glycemic levels within a narrow range, reflecting the recommendations of the Diabetes Control and Complications Trial . However, such tight glycemic control may not be feasible, and even patients who diligently regulate their blood glucose levels are still vulnerable to the many complications that characterize diabetes.
There are obvious therapeutic benefits to studying diabetic nephropathy and evaluating novel antidiabetic strategies that are capable of improving the chronic consequences of hyperglycemia.
In the present study, we provide evidence that HO-1 induction could confer protection against metabolic alterations and, at least in part, in kidney histological alterations observed in diabetic animals.
HO-1, the inducible isoform of the HO system, is a rate-limiting enzyme, which converts heme into equimolar amounts of iron, carbon monoxide, and biliverdin. HO-1 is thought to have antioxidant and cytoprotective roles . The products of the HO reaction, biliverdin and carbon monoxide, can be toxic at very high concentrations. However, recent evidence indicates that they are not toxic at physiological concentrations in normal cells, and that they may have important antioxidant, anti-inflammatory, or anti-apoptotic properties [31, 32].
The level of HO-1 protein is increased in diabetes. Our work demonstrated that in hyperglycemic rats treated with streptozotocin, the HO-1 expression in the kidneys was increased, and that in similar animals that were treated with hemin, the induction of HO-1 improved the histological alterations observed.
The hyperglycemia induced by streptozotocin promoted diuresis and inhibited weight gain. In our experiment, the treatment with hemin decreased blood glucose and urea, as already observed in other studies. Correa-Costa observed that hemin treatment improved the kidney function and reversed the fibrosis observed in chronic kidney disease induced by ureteral unilateral obstruction . Hemin improved the glucose metabolism in hyperglycemic and spontaneously hypertensive rats , and type 2 diabetic subjects showed an increase in HO-1 .
In streptozotocin-induced hyperglycemic rats, glomerular alterations such as microalbuminuria, increase in urea levels, and decrease in creatinine clearance, as well as tubular disorders, and increased excretion of sodium were observed. The treatment of hyperglycemic animals with hemin over 60 days inhibited the microalbuminuria, decreased urea levels, and induced a slight increase in creatinine clearance, but did not improve the level of sodium excretion. The effect of hemin on microalbuminuria has also been shown by others .
Our histological analysis showed that the renal tissues from diabetic animals treated with hemin were protected from the damage induced by hyperglycemia. Glomerulosclerosis was significantly inhibited and the fibrotic collagen deposition was prevented by hemin treatment.
The protective effects of HO-1 have been demonstrated in vivo; it was found that the induction of HO-1 in mice prevented diabetes-induced kidney injury. This effect resulted from oxidative stress inhibition . Additionally, the interaction between heme oxygenase and nitric oxide (NO) has already been observed in the kidney . The HO-1 induction inhibits NO synthase , however fewer works have demonstrated the interaction between these systems in the kidneys of diabetic animals. The present study showed that treatment with hemin also inhibited NO synthase expression and urinary nitric oxide production in 24-h urine, and the inhibition of NO could be involved in the protective effect of hemin.
Histological analysis showed that there was a prevention of tubular injury, fibrosis, induction of HO-1 and inhibition of iNOS and NO in those subjects that had been treated with hemin. This effect may result, in part, from inhibition of lipid peroxidation .
In conclusion, our data suggest that chronic induction of HO-1 reduces hyperglycemia, improves glucose metabolism in diabetic animals, and protects the renal tissue from hyperglycemic injury, possibly resulting from antioxidant activity.