NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Am J Physiol Renal Physiol. 2020 Jun 1;318(6):F1409-F1417. doi: 10.1152/ajprenal.00579.2019. Epub 2020 May 11.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate postprandial insulin release. However, GLP-1 also exerts extrapancreatic effects, including renal effects. Some of these renal effects are attenuated in hypertensive rats, where renal expression of GLP-1 receptors is reduced. Here, we assessed the expression and vascular function of GLP-1 receptors in kidneys from young prehypertensive rats. We also examined GLP-1-induced vasodilation in the renal vasculature in wild-type (WT) and GLP-1 receptor knockout mice using wire and pressure myography and the isolated perfused juxtamedullary nephron preparation. We investigated whether GLP-1 and the metabolite GLP-1(9-36)amide had renal vascular effects independent of the known GLP-1 receptor. We hypothesized that hypertension decreased expression of renal GLP-1 receptors. We also hypothesized that GLP-1-induced renal vasodilatation depended on expression of the known GLP-1 receptor. In contrast to normotensive rats, no immunohistochemical staining or vasodilatory function of GLP-1 receptors was found in kidneys from prehypertensive rats. In WT mice, GLP-1 induced renal vasodilation and reduced the renal autoregulatory response. The GLP-1 receptor antagonist exendin 9-39 inhibited relaxation, and GLP-1(9-36)amide had no vasodilatory effect. In GLP-1 receptor knockout mice, no relaxation induced by GLP-1 or GLP-1(9-36)amide was found, the autoregulatory response in afferent arterioles was normal, and no GLP-1-induced reduction of autoregulation was found. We conclude that in prehypertensive kidneys, expression and function of GLP-1 receptors is lost. The renal vasodilatory effect of GLP-1 is mediated exclusively by the known GLP-1 receptor. GLP-1(9-36)amide has no renal vasodilatory effect. GLP-1 attenuates renal autoregulation by reducing the myogenic response.
胰高血糖素样肽-1 (GLP-1) 是一种肠促胰岛素激素，已知可刺激餐后胰岛素释放。然而，GLP-1 还具有胰外作用，包括肾脏作用。在高血压大鼠中，这些肾脏作用中的一些被减弱，其中 GLP-1 受体的肾脏表达减少。在这里，我们评估了年轻高血压前期大鼠肾脏中 GLP-1 受体的表达和血管功能。我们还使用线描和压力描记术以及离体灌流髓旁肾单位制备检查了野生型 (WT) 和 GLP-1 受体敲除小鼠中 GLP-1 诱导的肾血管舒张作用。我们研究了 GLP-1 和 GLP-1(9-36)酰胺是否具有独立于已知 GLP-1 受体的肾脏血管作用。我们假设高血压降低了肾脏 GLP-1 受体的表达。我们还假设 GLP-1 诱导的肾血管舒张依赖于已知 GLP-1 受体的表达。与正常血压大鼠相比，高血压前期大鼠肾脏中未发现 GLP-1 受体的免疫组织化学染色或血管舒张功能。在 WT 小鼠中，GLP-1 诱导肾血管舒张并降低肾自身调节反应。GLP-1 受体拮抗剂 exendin 9-39 抑制松弛，GLP-1(9-36)酰胺没有血管舒张作用。在 GLP-1 受体敲除小鼠中，未发现 GLP-1 或 GLP-1(9-36)酰胺诱导的松弛，入球小动脉的自身调节反应正常，也未发现 GLP-1 诱导的自身调节反应减弱。我们得出结论，在高血压前期肾脏中，GLP-1 受体的表达和功能丧失。GLP-1 的肾血管舒张作用完全由已知的 GLP-1 受体介导。GLP-1(9-36)酰胺没有肾血管舒张作用。GLP-1 通过降低肌源性反应来减弱肾自身调节。
