Rescuing vascular dysfunction in dorsal pancreatic arteries prevents tacrolimus-induced glucose metabolism disorder in mice

TL;DR

Blocking the renin-angiotensin system with valsartan prevents tacrolimus-induced glucose metabolism issues in mice by improving pancreatic and renal vascular function.

Contribution

This study reveals a novel mechanism linking tacrolimus-induced vascular dysfunction to glucose metabolism disorder, and shows that RAS inhibition can prevent these effects.

Findings

Valsartan improves tacrolimus-induced hyperglycemia, hypoinsulinemia, and insulin resistance in mice.

Tacrolimus causes pancreatic islet dysfunction and β-cell loss, which are mitigated by valsartan.

Renal and pancreatic vascular dysfunction caused by tacrolimus is alleviated by RAS inhibition.

Abstract

Long-term adverse effects of the immunosuppressant tacrolimus (Tac), such as nephrotoxicity, hepatotoxicity and diabetes, have been widely reported. Up to 33.6% of solid organ transplantation patients receiving Tac treatment develop hyperglycemia; however, the underlying mechanisms remain poorly understood. 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 valsartan, a renin-angiotensin system (RAS) inhibitor. Histological and immunofluorescence analysis of the pancreas showed reduced islet areas and β-cell mass in Tac-treated mice. Moreover, when compared to control mice, isolated islets from Tac-treated mice showed a downregulation of cell-proliferation markers (Ki67, Ccna2 and Ccnd1) while an upregulation of apoptotic markers (DNA fragmentation, Bax and Caspase3). Tac also upregulated hypoxia-related markers in the pancreas, including hypoxia-inducible factor-1α (HIF-1α) and its downstream factors (Adm, Hmox1 and Vegfa), CD31 and pimonidazole adducts. Furthermore, treatment with Tac led to vascular dysfunction in pancreatic arteries. All of these adverse effects could be partially or fully abrogated by valsartan. Tac also increased levels of renin in renal tissue (1.00 ± 0.06 vs 1.29 ± 0.04, 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 Tac-induced vascular dysfunction in renal interlobar arteries. Collectively, our data illustrate a previously undescribed mechanism, in which Tac-induced vascular dysfunction in renal interlobar arteries leads to RAS activation. Blocking RAS by valsartan alleviates vascular dysfunction in dorsal pancreatic arteries and hypoxia in islets, which in turn prevents Tac-induced β-cell dysfunction and glucose metabolism disorder.

The online version contains supplementary material available at 10.1186/s10020-025-01282-7.

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