Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
J Mol Endocrinol. 2022 Mar 25;68(3):167-178. doi: 10.1530/JME-21-0199. Print 2022 Apr 1.
Beyond the CNS, urotensin II (UII) and its receptor (UT) are functionally expressed in peripheral tissues of the endocrine, cardiovascular, and renal systems. The expression levels of UII and UT in the kidney and circulating UII levels are increased in diabetes. UII also promotes mesangial proliferation and matrix accumulation in vitro. Here, we evaluate the effect of UT deletion on the development of hyperglycemia and diabetic kidney disease (DKD) in streptozotocin (STZ)-treated mice. Ten-week-old WT and UT knockout (KO) mice were injected with STZ for 5 days to induce diabetes. Blood glucose levels were measured weekly, and necropsy was performed 12 weeks after STZ injection. UT ablation slowed hyperglycemia and glucosuria in STZ-treated mice. UT KO also ameliorated STZ-induced increase in HbA1c, but not STZ-induced decrease in plasma insulin levels. However, STZ-induced increases in plasma glucagon concentration and immunohistochemical staining for glucagon in pancreatic islets were lessened in UT KO mice. UT ablation also protected against STZ-induced kidney derangements, including albuminuria, mesangial expansion, glomerular lesions, and glomerular endoplasmic reticulum stress. UT is expressed in a cultured pancreatic alpha cell line, and its activation by UII triggered membrane depolarization, T- and L-type voltage-gated Ca2+channel-dependent Ca2+influx, and glucagon secretion. These findings suggest that apart from direct action on the kidneys to cause injury, UT activation by UII may result in DKD by promoting hyperglycemia via induction of glucagon secretion by pancreatic alpha cells.
除中枢神经系统外，尿皮质素 II（UII）及其受体（UT）在外周内分泌、心血管和肾脏系统的组织中也具有功能性表达。糖尿病患者肾脏和循环中 UII 的表达水平以及 UII 水平升高。UII 还可促进体外系膜细胞增殖和基质堆积。在此，我们评估了 UT 缺失对链脲佐菌素（STZ）处理的小鼠发生高血糖和糖尿病肾病（DKD）的影响。10 周龄的 WT 和 UT 敲除（KO）小鼠接受 STZ 注射 5 天以诱导糖尿病。每周测量血糖水平，STZ 注射后 12 周进行尸检。UT 缺失可减缓 STZ 处理的小鼠的高血糖和糖尿。UT KO 还改善了 STZ 诱导的 HbA1c 升高，但不能改善 STZ 诱导的血浆胰岛素水平降低。然而，UT KO 小鼠中 STZ 诱导的胰高血糖素浓度升高和胰岛内胰高血糖素免疫组织化学染色减少。UT 缺失还可防止 STZ 诱导的肾脏异常，包括蛋白尿、系膜扩张、肾小球病变和肾小球内质网应激。UT 在培养的胰腺α细胞系中表达，其被 UII 激活后可引发膜去极化、T 型和 L 型电压门控 Ca2+通道依赖性 Ca2+内流和胰高血糖素分泌。这些发现表明，除了直接作用于肾脏引起损伤外，UT 通过诱导胰腺α细胞分泌胰高血糖素而导致高血糖，从而可能导致 DKD。
