Division of Nephrology, University of Washington School of Medicine , Seattle, Washington.
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute , Buffalo, New York.
Am J Physiol Renal Physiol. 2018 Jul 1;315(1):F97-F109. doi: 10.1152/ajprenal.00570.2017. Epub 2018 Feb 7.
Blocking the renin-angiotensin-aldosterone system (RAAS) remains a mainstay of therapy in hypertension and glomerular diseases. With the population aging, our understanding of renin-producing cells in kidneys with advanced age is more critical than ever. Accordingly, we administered tamoxifen to Ren1cCreERxRs-tdTomato-R mice to permanently fate map cells of renin lineage (CoRL). The number of Td-tomato-labeled CoRL decreased significantly in aged mice (24 mo of age) compared with young mice (3.5 mo of age), as did renin mRNA levels. To determine whether aged CoRL responded less to RAAS blockade, enalapril and losartan were administered over 25 days following uninephrectomy in young and aged mice. The number of CoRL increased in young mice in response to enalapril and losartan. However, this was significantly lower in aged mice compared with young mice due to limited proliferation, but not recruitment. Gene expression analysis of laser-captured CoRL showed a substantial increase in mRNA levels for proapoptotic and prosenescence genes, and an increase in a major prosenescence protein on immunostaining. These results show that CoRL are lower in aged mice and do not respond to RAAS inhibition to the same extent as young mice.
阻断肾素-血管紧张素-醛固酮系统（RAAS）仍然是高血压和肾小球疾病治疗的主要方法。随着人口老龄化，我们对老年肾脏中产生肾素的细胞的了解比以往任何时候都更加重要。因此，我们给 Ren1cCreERxRs-tdTomato-R 小鼠施用他莫昔芬以永久性地对肾素谱系细胞（CoRL）进行谱系示踪。与年轻小鼠（3.5 月龄）相比，老年小鼠（24 月龄）中 Td-tomato 标记的 CoRL 数量明显减少，肾素 mRNA 水平也是如此。为了确定老年 CoRL 对 RAAS 阻断的反应是否较低，我们在年轻和老年小鼠进行单侧肾切除术后的 25 天内给予依那普利和氯沙坦。依那普利和氯沙坦可使年轻小鼠中的 CoRL 数量增加。然而，与年轻小鼠相比，老年小鼠中的 CoRL 增加量明显较低，这是由于增殖受限而不是募集减少所致。对激光捕获的 CoRL 进行的基因表达分析显示，促凋亡和促衰老基因的 mRNA 水平显著增加，免疫染色显示主要的促衰老蛋白增加。这些结果表明，老年小鼠中的 CoRL 数量较低，并且对 RAAS 抑制的反应程度不如年轻小鼠。
