Estrogen-related receptor agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Background: A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation.Methods: ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). Pan-ERR agonist was used to treat 21-month-old mice for 8-weeks.Results: Remarkably, only an 8-week treatment with the pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1a, ERRa, mitochondrial complexes and MCAD expression.Conclusions: Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

背景：即便在健康衰老个体中，亦会出现肾功能的渐进性下降。除衰老本身外，衰老人群中高发的合并代谢综合征与高血压可诱导线粒体功能障碍与炎症反应，二者共同介导年龄相关性肾功能异常与肾脏疾病。本研究聚焦核激素受体家族中的雌激素相关受体（estrogen related receptors，ERRs）在年龄相关性线粒体功能障碍及炎症调控中的作用。
方法：衰老人类与小鼠的肾脏组织中ERRs表达水平下调，而终身热量限制（caloric restriction，CR）喂养的衰老小鼠肾脏中ERRs水平得以维持。本研究采用泛ERR激动剂对21月龄小鼠进行为期8周的干预治疗。
结果：令人惊喜的是，仅接受8周泛ERR激动剂干预即可逆转年龄相关性蛋白尿、足细胞丢失、线粒体功能障碍以及包括cGAS-STING与STAT3信号通路在内的炎症因子水平升高。此外，采用STING抑制剂对21月龄小鼠进行3周干预，不仅可逆转炎症因子与衰老标志物p21的水平升高，还意外逆转了年龄相关性的PGC-1α、ERRα、线粒体复合物及MCAD表达下调。
结论：本研究证实ERRs是年龄相关性线粒体功能障碍与炎症反应的重要调控因子。