Tian Lin, Li Cai, Qi Jiping, Fu Peng, Yu Xiaoyan, Li Xiaokun, Cai Lu
Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, P.R.China.
Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1234-42. doi: 10.1152/ajpendo.90672.2008. Epub 2008 Sep 16.
Urotensin II (UII) was identified as the ligand for a novel G protein-coupled receptor, GPR14. UII was found not only to have a potent vasoconstrictive action but also to have profibrotic effects in the heart. The present study was to define whether UII and GPR14 also play important roles in diabetes-induced renal fibrosis and dysfunction. Diabetic rats were induced using streptozotocin, and the rat proximal tubular epithelial cells (NRK-52E) were used for the in vitro mechanism study. Results showed that expression of UII and GPR14 was significantly upregulated at both mRNA and protein levels in the diabetic kidneys compared with controls. The upregulated expressions of UII and GPR14 in the kidney were accompanied by significant increases in the renal profibrotic factor transforming growth factor (TGF)-beta1 expression, the renal extracellular matrix (fibronectin and collagen IV) accumulation, and the renal dysfunction (increases in urinal N-acetyl-beta-d-glucosaminidase content, 24-h urinary retinol-binding protein excretion rate, and decrease in creatinine clearance rate). Exposure of NRK-52E cells to 10(-8) mol/l UII for 48 h caused a significant increase of TGF-beta1, but not ANG II, production that was GPR14- and calcium-dependent, since GPR14 small-interfering RNA and calcium channel blocker nimodipine or calcium chelator EDTA all could abolish the induction of TGF- beta1 by UII. Furthermore, exposure of NRK-52E cells to TGF-beta1 or ANG II also increased UII and GPR14 mRNA expressions. These results suggested that diabetes-induced upregulation of UII and GPR14, most likely through autocrine and/or paracrine mechanisms, plays an important role in TGF-beta1-mediated renal fibrosis and dysfunction.
尾加压素II（UII）被确定为一种新型G蛋白偶联受体GPR14的配体。人们发现UII不仅具有强大的血管收缩作用，而且在心脏中具有促纤维化作用。本研究旨在确定UII和GPR14在糖尿病诱导的肾纤维化和功能障碍中是否也发挥重要作用。使用链脲佐菌素诱导糖尿病大鼠，并使用大鼠近端肾小管上皮细胞（NRK-52E）进行体外机制研究。结果显示，与对照组相比，糖尿病肾脏中UII和GPR14的mRNA和蛋白水平均显著上调。肾脏中UII和GPR14的上调表达伴随着肾促纤维化因子转化生长因子（TGF）-β1表达的显著增加、肾细胞外基质（纤连蛋白和IV型胶原）的积累以及肾功能障碍（尿N-乙酰-β-D-氨基葡萄糖苷酶含量增加、24小时尿视黄醇结合蛋白排泄率增加以及肌酐清除率降低）。将NRK-52E细胞暴露于10^(-8) mol/l UII 48小时导致TGF-β1产生显著增加，但血管紧张素II（ANG II）产生未增加，这是GPR14和钙依赖性的，因为GPR14小干扰RNA以及钙通道阻滞剂尼莫地平或钙螯合剂乙二胺四乙酸（EDTA）均可消除UII对TGF-β1的诱导作用。此外，将NRK-52E细胞暴露于TGF-β1或ANG II也会增加UII和GPR14 mRNA表达。这些结果表明，糖尿病诱导的UII和GPR14上调，很可能通过自分泌和/或旁分泌机制，在TGF-β1介导的肾纤维化和功能障碍中起重要作用。
