Diabetes is associated with decreased epoxyeicosatrienoic acids (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase (sEH) inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the crosstalk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin (STZ)-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of AUDA in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced ROS production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of the VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4.

中文翻译：

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VEGF-A：CYP2C 衍生的 EET 和 NOX4 在糖尿病肾病中的新机制联系

糖尿病与环氧二十碳三烯酸 (EET) 生物利用度降低和肾小球血管内皮生长因子 A (VEGF-A) 表达水平升高有关。我们检查了可溶性环氧化物水解酶 (sEH) 抑制剂是否可以预防糖尿病肾病的病理变化，以及抑制 VEGF-A 信号通路是否会减轻糖尿病引起的肾小球损伤。我们还旨在描述细胞色素 P450 2C (CYP2C) 衍生的 EET 和 VEGF-A 之间的串扰。链脲佐菌素 (STZ) 诱导的 1 型糖尿病 (T1D) 大鼠在饮用水中加入 25 mg/L AUDA 治疗 6 周。在平行实验中，T1D 大鼠用 SU5416 或人源化单克隆抗 VEGF-A 中和抗体治疗 8 周。处理后，大鼠被安乐死，分离肾皮质用于进一步分析。AUDA 治疗减轻了糖尿病引起的肾功能下降。此外，AUDA 治疗降低了糖尿病相关的氧化应激和 NADPH 氧化酶活性。有趣的是，发现 CYP2C11 衍生的 EET 形成的下调与 VEGF-A 信号通路的激活相关。事实上，使用抗 VEGF 或 SU5416 抑制 VEGF-A 通过抑制 Nox4 诱导的 ROS 产生显着减轻糖尿病诱导的肾小球损伤。这些发现在糖尿病环境中培养的大鼠和人类足细胞中得到了体外复制。总之，我们的结果表明高血糖引起的肾小球损伤是由 CYP2C11 衍生的 EET 形成下调介导的，随后是 VEGF-A 信号的激活和 Nox4 的上调。据我们所知，这是第一项强调 VEGF-A 作为 CYP2C11 衍生的 EET 生产和 Nox4 之间的机制联系的研究。