Supplemental Digital Content is available in the text. GPR81 (G-protein-coupled receptor 81) is highly expressed in adipocytes, and activation by the endogenous ligand lactate inhibits lipolysis. GPR81 is also expressed in the heart, liver, and kidney, but roles in nonadipose tissues are poorly defined. GPR81 agonists, developed to improve blood lipid profile, might also provide insights into GPR81 physiology. Here, we assessed the blood pressure and renal hemodynamic responses to the GPR81 agonist, AZ′5538. In male wild-type mice, intravenous AZ′5538 infusion caused a rapid and sustained increase in systolic and diastolic blood pressure. Renal artery blood flow, intrarenal tissue perfusion, and glomerular filtration rate were all significantly reduced. AZ′5538 had no effect on blood pressure or renal hemodynamics in Gpr81−/− mice. Gpr81 mRNA was expressed in renal artery vascular smooth muscle, in the afferent arteriole, in glomerular and medullary perivascular cells, and in pericyte-like cells isolated from kidney. Intravenous AZ′5538 increased plasma ET-1 (endothelin 1), and pretreatment with BQ123 (endothelin-A receptor antagonist) prevented the pressor effects of GPR81 activation, whereas BQ788 (endothelin-B receptor antagonist) did not. Renal ischemia-reperfusion injury, which increases renal extracellular lactate, increased the renal expression of genes encoding ET-1, KIM-1 (Kidney Injury Molecule 1), collagen type 1-α1, TNF-α (tumor necrosis factor-α), and F4/80 in wild-type mice but not in Gpr81−/− mice. In summary, activation of GPR81 in vascular smooth muscle and perivascular cells regulates renal hemodynamics, mediated by release of the potent vasoconstrictor ET-1. This suggests that lactate may be a paracrine regulator of renal blood flow, particularly relevant when extracellular lactate is high as occurs during ischemic renal disease.

中文翻译：

---

Endothelin-1 介导 GPR81 激活的全身和肾脏血流动力学影响

补充数字内容在文本中可用。GPR81（G 蛋白偶联受体 81）在脂肪细胞中高度表达，内源性配体乳酸的激活抑制脂肪分解。GPR81 也在心脏、肝脏和肾脏中表达，但在非脂肪组织中的作用尚不清楚。GPR81 激动剂，开发用于改善血脂谱，也可能提供对 GPR81 生理学的见解。在这里，我们评估了对 GPR81 激动剂 AZ'5538 的血压和肾血流动力学反应。在雄性野生型小鼠中，静脉注射 AZ'5538 导致收缩压和舒张压快速且持续升高。肾动脉血流量、肾内组织灌注和肾小球滤过率均显着降低。AZ'5538 对 Gpr81-/- 小鼠的血压或肾血流动力学没有影响。Gpr81 mRNA 在肾动脉血管平滑肌、传入小动脉、肾小球和髓质血管周围细胞以及从肾脏分离的周细胞样细胞中表达。静脉注射 AZ'5538 增加血浆 ET-1（内皮素 1），并且用 BQ123（内皮素-A 受体拮抗剂）预处理可阻止 GPR81 激活的升压作用，而 BQ788（内皮素-B 受体拮抗剂）则没有。肾缺血再灌注损伤会增加肾细胞外乳酸，增加编码 ET-1、KIM-1（肾损伤分子 1）、1-α1 型胶原、TNF-α（肿瘤坏死因子-α）的基因的肾表达，和 F4/80 在野生型小鼠中，但在 Gpr81-/- 小鼠中没有。总之，血管平滑肌和血管周围细胞中 GPR81 的激活调节肾血流动力学，通过释放有效的血管收缩剂 ET-1 介导。这表明乳酸可能是肾血流量的旁分泌调节剂，尤其是在缺血性肾病期间细胞外乳酸升高时尤其重要。