Meyer Matthias R, Rosemann Thomas, Barton Matthias, Prossnitz Eric R
Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Pharmacology. 2017;100(3-4):188-193. doi: 10.1159/000478732. Epub 2017 Jul 14.
Aging is associated with impaired renal artery function, which is partly characterized by arterial stiffening and a reduced vasodilatory capacity due to excessive generation of reactive oxygen species by NADPH oxidases (Nox). The abundance and activity of Nox depends on basal activity of the heptahelical transmembrane receptor GPER; however, whether GPER contributes to age-dependent functional changes in renal arteries is unknown. This study investigated the effect of aging and Nox activity on renal artery tone in wild-type and GPER-deficient (Gper-/-) mice (4 and 24 months old). In wild-type mice, aging markedly impaired endothelium-dependent, nitric oxide (NO)-mediated relaxations to acetylcholine, which were largely preserved in renal arteries of aged Gper-/- mice. The Nox inhibitor gp91ds-tat abolished this difference by greatly enhancing relaxations in wild-type mice, while having no effect in Gper-/- mice. Contractions to angiotensin II and phenylephrine in wild-type mice were partly sensitive to gp91ds-tat but unaffected by aging. Again, deletion of GPER abolished effects of Nox inhibition on contractile responses. In conclusion, basal activity of GPER is required for the age-dependent impairment of endothelium-dependent, NO-mediated relaxation in the renal artery. Restoration of relaxation by a Nox inhibitor in aged wild-type but not Gper-/- mice strongly supports a role for Nox-derived reactive oxygen species as the underlying cause. Pharmacological blockers of GPER signaling may thus be suitable to inhibit functional endothelial aging of renal arteries by reducing Nox-derived oxidative stress and, possibly, the associated age-dependent deterioration of kidney function.
衰老与肾动脉功能受损有关，其部分特征是动脉僵硬以及由于烟酰胺腺嘌呤二核苷酸磷酸氧化酶（Nox）过度产生活性氧而导致血管舒张能力降低。Nox的丰度和活性取决于七螺旋跨膜受体GPER的基础活性；然而，GPER是否导致肾动脉随年龄增长的功能变化尚不清楚。本研究调查了衰老和Nox活性对野生型和GPER缺陷型（Gper-/-）小鼠（4个月和24个月大）肾动脉张力的影响。在野生型小鼠中，衰老显著损害了内皮依赖性、一氧化氮（NO）介导的对乙酰胆碱的舒张反应，而在老年Gper-/-小鼠的肾动脉中这种反应基本保留。Nox抑制剂gp91ds-tat通过极大增强野生型小鼠的舒张反应消除了这种差异，而对Gper-/-小鼠没有影响。野生型小鼠对血管紧张素II和去氧肾上腺素的收缩反应部分对gp91ds-tat敏感，但不受衰老影响。同样，GPER的缺失消除了Nox抑制对收缩反应的影响。总之，GPER的基础活性是肾动脉中内皮依赖性、NO介导的舒张随年龄增长受损所必需的。Nox抑制剂在老年野生型而非Gper-/-小鼠中恢复舒张反应，有力地支持了Nox衍生的活性氧作为潜在原因的作用。因此，GPER信号通路的药理阻断剂可能适合通过减少Nox衍生的氧化应激以及可能相关的随年龄增长的肾功能恶化来抑制肾动脉功能性内皮衰老。
