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Abstract
People with diabetes are at increased risk of cardiovascular, cerebrovascular diseases, retinopathy with potential blindness, and nephropathy that may lead to renal failure. Strict control of blood glucose and blood pressure levels sometimes fail to delay the development of diabetic nephropathy, and an effective therapy is not yet available. Erythropoietin is a glycoprotein hormone produced primarily in the kidney. The essential function of erythropoietin is regulation of red blood cells production. In addition to being a hematopoietic factor, erythropoietin has multiple protective effects, such as antiapoptotic, antioxidant, anti-inflammatory, and angiogenic effects. The aim of the present study was carried out to investigate the role of erythropoietin in kidney dysfunction in diabetic rats as well as to determine the effect of erythropoietin on transactivation of hypoxia inducible factor 1-alpha (protect organs against hypoxia) in diabetic rats. The study was carried out on 40 albino rats weighing 200–250 gm. Thirty rats were diabetic by single intraperitoneal injection of streptozotocin (55 mg/kg ) dissolved in 0.01 mmol/l sodium citrate buffer at pH=4.5.
The rats were divided into four groups:
Group I (Normal Control): Ten non-diabetic rats served as controls & received a single intraperitoneal dose of sodium citrate at pH = 4.5.
Group II(Diabetic Control): Ten diabetic rats were given subcutaneous injections of saline every 2 days for 2 weeks (a total of 6 injections) starting the first dose on the same day of diagnosing diabetes.
Group III(Preventive Diabetic Group): Ten diabetic rats were given subcutaneous injections of 100 IU/kg recombinant human erythropoietin (EPO) every 2 days for 2 weeks (a total of 6 injections) starting the first dose on the same day of diagnosing diabetes.
Group IV (Treated Diabetic Group): Ten diabetic rats showing proteinuria were given subcutaneous injections of 100 IU/kg recombinant human EPO every 2 days for 2 weeks (a total of 6 injections) starting the first dose 2 weeks after diagnosing diabetes.
The study period was 4 weeks, the following parameters were measured:
1.Blood glucose level was measured weekly for assessment of diabetic state.
2.24 hours urinary concentration of total protein was measured at end of each week for four weeks by colorimetric assays for assessment of diabetic nephropathy.
3.Serum urea level was measured weekly for assessment of kidney function.
4.Serum and urinary creatinine level was measured weekly at the same time to calculate creatinine clearance.
5.At the end of study period the rats were sacrificed and HIF-1α was measured in the renal tissue by ELISA kit. In diabetic control group, blood glucose level was significantly increased due to the cytotoxic effect of Streptozotocin on pancreatic beta cells. Protein in urine was significantly increased which indicate diabetic nephropathy. Serum urea and creatinine clearance was significantly increased than normal control group which indicate deterioration of kidney disease. In erythropoietin supplemented diabetic groups (preventive diabetic and treated diabetic) serum urea, urinary protein and creatinine clearance were significantly decreased than control diabetic group but higher than in normal control group. However, erythropoietin has no role in controlling hyperglycemia in diabetic rats. Regarding the renal HIF-1 α, in this study, HIF-1 α levels showed significant increase 4 weeks after induction of diabetes in groups (II, III & IV) when compared to normal control gp (I). However, erythropoietin-supplied groups (preventive gp II and treated diabetic gp III) had significantly higher levels than diabetic control group. It seems that the improvement in renal function in erythropoietin supplemented groups may be due to increase in HIF-1α levels.