Increased renal production of angiotensin II and thromboxane B₂ in conscious diabetic rats

Background: The mechanisms involved in development of cardiovascular complications associated with diabetes mellitus are not well elucidated. Among the vasoactive factors that may play a role in development of these complications are angiotensin II and thromboxane B₂ (TXB ₂). We hypothesized that diabetes increases renal production of TXB₂ through stimulation of angiotensin type-1 receptor. Methods: We used a microdialysis technique to monitor changes in renal interstitial fluid (RIF) TXB₂ in conscious streptozotocin-induced diabetes rat model. The RIF levels of angiotensin II and TXB₂ were monitored before and during 6 weeks after development of diabetes and during treatment with the angiotensin type-1 receptor blocker valsartan at 10 mg/kg. Measurement of the urinary albumin excretion (UAE) was used to monitor the development and progression of diabetic nephropathy. Results: The UAE was 81.62 ± 1.31 ng/min, 184.75 ± 9.41 ng/min (P <. 01), and 229.84 ± 4.49 ng/min (P <. 0001) at baseline, week 3, and week 6, respectively, after induction of diabetes. Basal levels of RIF angiotensin II were 4.28 ± 0.02 pg/mL and significantly increased to 6.24 ± 0.31 pg/mL (P <. 001) and 7.66 ± 0.05 pg/mL (P <. 001) at 3 and 6 weeks after development of diabetes. Similarly, basal RIF TXB₂ was 197 ± 27 pg/mL and increased to 488 ± 80 pg/mL (P <. 01) and 703 ± 130 pg/mL (P <. 01) at 3 and 6 weeks after development of diabetes. Valsartan caused further increase in RIF angiotensin II levels. In contrast, valsartan decreased RIF TXB₂ levels at baseline to 85 ± 11 pg/mL (P <. 01), at 3 weeks to 141 ± 17 pg/mL (P <. 01), and at 6 weeks to 255 ± 45 pg/mL (P <. 01) after development of diabetes. Conclusions: These results demonstrate that diabetes mellitus is accompanied by increased renal production of angiotensin II and TXB₂. The increase in TXB₂ is mediated through stimulation of angiotensin type-1 receptor.