Effects of thromboxane prostanoid receptor deficiency on diabetic nephropathy induced by high fat diet and streptozotocin in mice
Effects of thromboxane prostanoid receptor deficiency on diabetic nephropathy induced by high fat diet and streptozotocin in mice
复制标题
血栓素前列腺素受体缺陷对高脂饮食和链脲佐菌素诱导的小鼠糖尿病肾病的影响
DOI：
10.1016/j.ejphar.2020.173254
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发表时间：
2020-09-05
影响因子：
5
通讯作者：
Zhou, Yingbi
中科院分区：
文献类型：
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作者：
Cai, Juyu;Liu, Bin;Zhou, Yingbi
糖尿病肾病（diabetic nephropathy，DN）是终末期肾病的主要病因之一，是临床治疗的一大难题。本研究旨在确定血栓素（TX）前列腺素受体（TP）（介导所有前列腺素的收缩活动）的缺乏是否会加速DN的发生，如果是这样，则检查其潜在机制。通过高脂饮食和链脲佐菌素注射在野生型（WT）小鼠和TP缺乏（TP-/-）小鼠中诱导糖尿病。在这里，我们表明，WT和TP-/-小鼠发展糖尿病具有相似的血糖水平，但是，肾功能损害和病理的迹象发生在TP-/-比WT小鼠在较小的程度。此外，TP-/-小鼠糖尿病肾皮质中转化生长因子-β 1（TGF-β 1）（DN的常见病理介质）表达水平的增加程度低于WT对应小鼠。此外，我们注意到，与非糖尿病患者相比，糖尿病患者肾皮质中环氧合酶（考克斯）-2和钙依赖性磷脂酶A（2）（cPLA（2））的表达水平以及前列腺素E-2和TXA（2）的水平均升高。因此，这些结果表明，可能由于上调cPLA（2）和考克斯-2导致糖尿病肾皮质中前列腺素类合成增加，TP-/-阻止DN的发展。此外，我们的研究结果表明，TP-/-的这种作用可能与抑制TGF-β 1的上调有关，而TGF-β 1的上调通常与疾病有关。
Diabetic nephropathy (DN), one of the main causes of end-stage renal disease, still remains as a challenge of clinical management. This study aimed to determine whether deficiency of the thromboxane (TX) prostanoid receptor (TP), which mediates the contractile activities of all prostanoids, alleviates the development of DN and if so, to examine the underlying mechanism(s). Diabetes was induced by high fat diet and streptozotocin injection in wild-type (WT) mice and those with TP deficiency (TP-/-). Here we show that WT and TP-/- mice developed diabetes with a similar blood glucose level; however, signs of renal functional impairments and pathologies occurred to a lesser extent in TP-/- than in WT mice. Also, the extent of an increase in the expression level of transforming growth factor-beta 1 (TGF-beta 1), a common pathological mediator of DN, in diabetic renal cortexes of TP-/- mice was lower than that of WT counterparts. Moreover, we noted that expression levels of cyclooxygenase (COX)-2 and calcium-dependent phospholipase A(2) (cPLA(2)) as well as levels of prostaglandin E-2 and TXA(2) in diabetic renal cortexes were increased as compared to those of non-diabetic conditions. These results thus demonstrate that possibly due to up-regulated cPLA(2) and COX-2 that lead to increased prostanoid syntheses in diabetic renal cortexes, TP-/- alleviates DN development. In addition, our results suggest that such an effect of TP-/- might be related to the suppression of TGF-beta 1 up-regulation that is commonly associated with the disease condition.