Scholarlink

<p>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, <i>p</i> &lt; 0.05) and serum (28.35 ± 4.29&#xa0;ng/mL vs 51.99 ± 4.95&#xa0;ng/mL, <i>p</i> &lt; 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月11日

查看全文
  • Lingyan Fei,
  • Honghong Wang,
  • Dongliang Zhao,
  • Xiaohua Wang,
  • Jizhen Ren,
  • Lanyun Liu,
  • Chun Tang,
  • Yan Lei,
  • Qingqing Wang,
  • Yuanpeng Nie,
  • Yang Liu,
  • Na Li,
  • Ming Zhong,
  • Nan Xu,
  • Jin Wei,
  • Pontus B. Persson,
  • Andraes Patzak,
  • Pratik H. Khedkar,
  • Zhihua Zheng,
  • Shan Jiang

摘要

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.