jabbrv-ltwa-all.ldf jabbrv-ltwa-en.ldf Long-term use of the immunosuppressant tacrolimus (Tac) is limited due to its nephrotoxic, hepatotoxic and diabetogenic effects. Up to 33.6% of solid organ transplantation patients receiving Tac treatment develop hyperglycemia; however, the underlying mechanisms remain poorly elucidated. Here, using a mouse model of Tac-induced hyperglycemia, we found that Tac-induced body-weight loss, hyperglycemia, hypoinsulinemia, glucose intolerance and insulin resistance were improved by a renin-angiotensin system (RAS) inhibitor (valsartan). Morphologic and immunofluorescence observation uncovered that the pancreatic islet areas and β cell mass were reduced in Tac-treated mice. Besides, in isolated islets from Tac-treated mice, markers of cell proliferation (Ki67, Ccna2 and Ccnd1) were downregulated but markers of cell apoptosis (DNA fragmentation, Bax and Caspase3) were upregulated compared with control mice. Hypoxia-related markers in pancreas, including hypoxia-inducible factor-1 (HIF-1) and its downstream factors (Adm, Hmox1 and Vegfa), CD31 and pimonidazole adducts were augmented by Tac. Treatment with Tac leaded to vascular dysfunction in pancreatic arteries. All of these adverse effects could be partly or fully restored by valsartan. Tac also increased levels of renin in renal tissue (1.00±0.06 vs 1.31±0.02, p<0.05) and serum (28.35±4.29 ng/mL vs 51.99±4.95 ng/mL, p<0.05). Inhibition of RAS by valsartan protected against vascular dysfunction induced by Tac in renal interlobar arteries. Collectively, our data illustrate a previously undescribed mechanism that Tac-induced vascular dysfunction in renal interlobar arteries leads to RAS activation. Blocking RAS by valsartan alleviated vascular dysfunction in dorsal pancreatic arteries and hypoxia in islets, which in turn prevents Tac-induced β-cell dysfunction and glucose metabolism disorder.