Abstract
Objective: Inhibition of the renin-angiotensin system (RAS) with ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) is associated with concentric thickening of renal arteries and arterioles and parenchymal disease. Here we evaluated to what degree this also occurs during RAS inhibition with siRNA targeting hepatic angiotensinogen (AGT). Methods: Male hypertensive heterozygous transgenic rats overexpressing mouse renin (TGR(mRen2)27 rats), made diabetic with streptozotocin, were treated with the ARB valsartan (4 mg/kg/day), the ACEi captopril (6 mg/kg/day), AGT siRNA (30 mg/kg every 2 weeks), AGT siRNA + valsartan, or captopril+valsartan for 3 weeks, starting at 15 weeks after induction of diabetes. After 3 weeks of treatment, kidneys were removed, and immunocytochemistry was performed on Bouin's fixed kidney sections using antibodies against renin or α-smooth muscle actin. Juxtaglomerular index and wall thickness were assessed using tiling pictures of both renin and α-smooth muscle actin sections from the slides. Tubular degeneration was scored by summing up scores for tubular atrophy, interstitial fibrosis, and tubulointerstitial inflammation. Concentric vascular hypertrophy was assessed in a blinded manner. Results: All treatments increased juxtaglomerular index, and the largest increases were observed in dual treatment groups, consistent with the highest degree of RAS blockade in these groups. Tubular scores increased after induction of diabetes, and the highest scores were seen in dual treatment groups, significance versus vehicle being reached in the valsartan+captopril group only (P<0.05). Afferent arteriole wall thickness increased in all treatment groups, and the greatest increases were observed during dual treatment. Finally, concentric vascular hypertrophy was observed in 1 of 7 diabetic Ren2 rats; this percentage increased during RAS blocker treatment of these rats, numerically reaching the highest values during dual treatment. Conclusions: Our data suggest that, in the hypertensive diabetic rat model, high levels of RAS blockade, irrespective of the type of blockade, may result in an increase in afferent arteriole thickness and concentric vascular hypertrophy. AGT siRNA in combination with RAS inhibitors should be further explored in clinical studies.
Published Version
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