Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
Kidney Int. 2020 Jan;97(1):143-155. doi: 10.1016/j.kint.2019.07.028. Epub 2019 Sep 5.
In the setting of type-2 diabetes, there are declines of structural stability and functionality of blood capillaries and red blood cells (RBCs), increasing the risk for microcirculatory disturbances. Correcting hyperglycemia is not entirely effective at reestablishing normal cellular metabolism and function. Therefore, identification of pathological changes occurring before the development of overt hyperglycemia may lead to novel therapeutic targets for reducing the risk of microvascular dysfunction. Here we determine whether RBC-capillary interactions are altered by prediabetic hypersecretion of amylin, an amyloid forming hormone co-synthesized with insulin, and is reversed by endothelial cell-secreted epoxyeicosatrienoic acids. In patients, we found amylin deposition in RBCs in association with type-2 diabetes, heart failure, cancer and stroke. Amylin-coated RBCs have altered shape and reduced functional (non-glycated) hemoglobin. Amylin-coated RBCs administered intravenously in control rats upregulated erythropoietin and renal arginase expression and activity. We also found that diabetic rats expressing amyloid-forming human amylin in the pancreas (the HIP rat model) have increased tissue levels of hypoxia-inducible transcription factors, compared to diabetic rats that express non-amyloid forming rat amylin (the UCD rat model). Upregulation of erythropoietin correlated with lower hematocrit in the HIP model indicating pathologic erythropoiesis. In the HIP model, pharmacological upregulation of endogenous epoxyeicosatrienoic acids protected the renal microvasculature against amylin deposition and also reduced renal accumulation of HIFs. Thus, prediabetes induces dysregulation of amylin homeostasis and promotes amylin deposition in RBCs and the microvasculature altering RBC-capillary interaction leading to activation of hypoxia signaling pathways and pathologic erythropoiesis. Hence, dysregulation of amylin homeostasis could be a therapeutic target for ameliorating diabetic vascular complications.
在 2 型糖尿病的情况下，血液毛细血管和红细胞（RBC）的结构稳定性和功能下降，增加了微循环紊乱的风险。纠正高血糖并不能完全有效地恢复正常细胞代谢和功能。因此，识别在显性高血糖发生之前发生的病理变化可能会为降低微血管功能障碍的风险提供新的治疗靶点。在这里，我们确定了胰岛素共合成的淀粉样形成激素胰淀素的糖尿病前期高分泌是否会改变 RBC-毛细血管相互作用，以及内皮细胞分泌的环氧化物三烯酸是否可以逆转这种作用。在患者中，我们发现 RBC 中存在与 2 型糖尿病、心力衰竭、癌症和中风相关的胰淀素沉积。带胰淀素涂层的 RBC 形状发生改变，功能性（非糖化）血红蛋白减少。在对照大鼠中静脉内给予带胰淀素涂层的 RBC 会上调促红细胞生成素和肾精氨酸酶的表达和活性。我们还发现，在胰腺中表达淀粉样形成人胰淀素的糖尿病大鼠（HIP 大鼠模型）与表达非淀粉样形成大鼠胰淀素的糖尿病大鼠（UCD 大鼠模型）相比，组织中缺氧诱导转录因子的水平增加。在 HIP 模型中，促红细胞生成素的上调与较低的血细胞比容相关，表明存在病理性红细胞生成。在 HIP 模型中，内源性环氧化物三烯酸的药理学上调可防止胰淀素在肾脏微血管中的沉积，并减少 HIF 在肾脏中的积累。因此，糖尿病前期会导致胰淀素动态平衡失调，促进 RBC 中胰淀素的沉积，并改变 RBC-毛细血管相互作用，导致缺氧信号通路的激活和病理性红细胞生成。因此，胰淀素动态平衡失调可能是改善糖尿病血管并发症的治疗靶点。
