Evidence of Angiotensin II (ANG II) and Endothelin‐1 (ET‐1) participation in vascular complications of diabetes via JAK2

ANG II and ET-1 are implicated in the complications of diabetes. In this study we tested the hypothesis that the JAK/STAT pathway is involved in the development of diabetic complications. Utilizing male Sprague-Dawley rats we performed a time course study (days 7, 14 and 28 post-STZ injection). Aortas were removed, protein isolated and standard Western techniques utilized. On day 7 there was no increase in phosphorylation of JAK2, STAT1 and STAT3 but on days 14 and 28 phosphorylation levels of all three were significantly increased. This was inhibited by treatment with the AT1 receptor antagonist candesartan, the ETA receptor antagonist ABT-627 and the JAK2 inhibitor AG490. Urinary protein excretion significantly increased on days 14 and 28, which was inhibited by treatment with candesartan, ABT-627 and AG490. Only on day 28 there was a significant increase in the blood pressure in the STZ diabetic rats that was inhibited by the treatment with candesartan, ABT-627 and AG490. Furthermore, in isolated tissue bath studies we found that treatment of rats with AG490 for 14 days restored the endothelium dependant relaxation in the STZ diabetic aorta preconstricted with KCl. On day 28 there was a significant inhibition of the endothelium- dependent relaxation in the aorta from the diabetic STZ rats which was attenuated by treatment with AG490 (95%, 40% and 77% relaxed in Sham, STZ and STZ with AG490 treatment, respectively). Therefore, we conclude that ANG II and ET-1 are both activating JAK2 in vivo in diabetes which may participate in the development of vascular complications. NIH Grants HL58139, DK50268 (MBM), HL64776 (DMP), AHA SDG (ABB).