Doxazosin Prevents Proteinuria and Glomerular Loss of Heparan Sulfate in Diabetic Rats

Abstract

We examined whether blood pressure reduction or good glycemic control equally lower albuminuria by preventing glomerular loss of heparan sulfate and progression of glomerulosclerosis in streptozotocin-induced diabetic rats. We used doxazosin, and alpha 1-adrenergic blocker, to lower systemic blood pressure, and good glycemic control was achieved by insulin treatment. Rats were killed after 20 weeks of treatment. Doxazosin significantly lowered systolic pressure in diabetic rats; however, it had no effect in normal rats. Good glycemic control also lowered systolic pressure. In diabetic rats with good glycemic control, doxazosin had an additive effect on blood pressure. Glomerular heparan sulfate synthesis was significantly lower and urinary albumin excretion higher in diabetic than in normal rats. Both doxazosin treatment and good glycemic control normalized these abnormalities in diabetic rats. Insulin normalized plasma glucose and glycosylated HbA1 concentrations in diabetic rats, as did doxazosin. Significant increases in mesangial area and glomeruloscelerosis were observed in diabetic rats. Only good glycemic control normalized these pathological changes in all diabetic rats. Two-way factorial ANOVA showed an interaction between the effects of doxazosin and insulin on systolic pressure and plasma glucose. The data show that after 20 weeks of doxazosin treatment, albuminuria was reduced by 80%; however, this treatment had no significant effect on mesangial expansion or progression to glomerulosclerosis. Conversely, good glycemic control prevented all three of the preceding sequelae.

Effect of Antihypertensive Therapy on Renal Injury in Type 2 Diabetic Rats With Hypertension

“…However, combination therapy was superior to either DZN or LIS treatment in preventing glomerular sclerosis in these rats. The observed effect of DZN in lowering blood glucose levels in the present as well as a previous study 17 is an important finding that warrants extensive investigation in diabetic subjects.…”

“…17 In addition, DZN was found to lower plasma glucose in these diabetic rats. Drug treatment began 1 week after induction of diabetes; therefore, DZN improved albuminuria and plasma glucose by attenuating the rise in blood pressure.…”

“…17 The mechanism by which DZN improves plasma glucose is unclear. However, DZN has been shown to lower plasma glucose and insulin levels without altering glycosylated HbA 1 in type 2 diabetics with hypertension after 6 weeks of treatment.…”

“…[7][8][9] Among antihypertensive drugs, the angiotensinconverting enzyme (ACE) inhibitors were found to be therapeutically more efficacious in protecting the kidney than other groups of antihypertensive drugs. 2,10 -13 However, some calcium blockers, 14 -16 ␣ 1 -blockers, 17,18 and ␤-blockers 12,19 were also found to prevent proteinuria in diabetic patients and animals.…”

Renoprotective Effect of Angiotensin-Converting Enzyme Inhibitor Combined with α1-Adrenergic Antagonist in Spontaneously Hypertensive Rats with Renal Ablation

“…The decreased nitric oxide synthase (NOS) activity in the kidney of L-NAME-induced hypertensive rats was significantly increased by DOX, and this increase may play a role in the prevention of glomerulosclerosis. Furthermore, Tsai et al (36) reported that DOX inhibits both serum-stimulated and platelet-derived growth factor-induced rat mesangial cell proliferation, and Jyothirmayi et al (37) reported evidence that treatment with DOX may prevent leakage of albumin through the glomerular basement membrane in diabetic rats. Further studies will be needed to confirm the efficacy of combination therapy using an ACEI with an α1-adrenergic antagonist.…”