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1 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, USA
* To whom correspondence should be addressed. E-mail: mmarrero{at}mail.mcg.edu.
Clinical and animal studies show that treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists slows progression of nephropathy in diabetes, indicating Ang II plays an important role in its development. We previously reported that hyperglycemia augments both Ang II-induced growth and activation of JAK2 and STAT proteins in cultured rat mesangial cells. Furthermore, we demonstrated that the tyrosine kinase enzyme JAK2 plays a key role in both Ang II- and hyperglycemia-induced growth in these cells. We hypothesized that the ACE inhibitor, captopril, and the Ang II receptor antagonist candesartan would hinder hyperglycemic-induced activation of JAK and STAT proteins in rat glomeruli, demonstrating that Ang II plays an important role in the activation of these proteins in vivo. Adult male Sprague-Dawley rats were given either streptozotocin (STZ; 60 mg/Kg) or vehicle, i.v., and glomeruli were isolated 2 wk later. Activation of JAK and STAT proteins was evaluated by Western blot analysis for specific tyrosine phosphorylation. Groups of rats were given: captopril (75-85 mg/Kg/day), candesartan (10 mg/Kg/day) or the JAK2 inhibitor AG490 (5 mg/Kg/day)for the study's duration. STZ stimulated glomerular phosphorylation of JAK2, STAT1, STAT3 and STAT5. Phosphorylation was reduced in rats treated with captopril, candesartan and AG490. Furthermore, both candesartan and AG490 inhibited STZ-induced increases in urinary protein excretion. In conclusion, our studies demonstrate that hyperglycemia induces activation of JAK2 and the STATs in vivo via an Ang II dependent mechanism and that these proteins may be involved in the early kidney damage associated with diabetes.
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