Department of Pediatrics, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
Department of Pediatrics, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
Exp Mol Pathol. 2020 Dec;117:104551. doi: 10.1016/j.yexmp.2020.104551. Epub 2020 Sep 30.
Cellular senescence is important for the maintenance of tissue homeostasis during normal development. In this study, we aimed to investigate the effect of renin angiotensin system (RAS) blockade on renal cell senescence in the developing rat kidney. Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for seven days after birth. We investigated the intrarenal expressions of cell cycle regulators p21 and p16 with immunoblots and immunohistochemistry at postnatal day 8. For the determination of renal cellular senescence, immunostaining for senescence-associated β-galactosidase (SA-β-gal) and telomerase reverse transcriptase (TERT) was also performed. Enalapril treatment showed significant alterations in cellular senescence in neonatal rat kidneys. In the enalapril-treated group, intrarenal p16 and p21 protein expressions decreased compared to controls. The expressions of both p21 and p16 were reduced throughout the renal cortex and medulla of enalapril-treated rats. The immunoreactivity of TERT in enalapril-treated kidneys was also weaker than that in control kidneys. Control kidneys revealed a clear positive SA-β-gal signal in the cortical tubules; however, SA-β-gal activity was noticeably lower in the enalapril-treated kidneys than in control kidneys. Interruption of the RAS during postnatal nephrogenesis may disrupt physiologic renal cellular senescence in the developing rat kidney.
细胞衰老对于正常发育过程中组织内稳态的维持非常重要。在这项研究中，我们旨在研究肾素-血管紧张素系统（RAS）阻断对发育中大鼠肾脏细胞衰老的影响。新生大鼠在出生后 7 天内接受依那普利（30mg/kg/天）或载体处理。我们在出生后第 8 天通过免疫印迹和免疫组织化学法检测细胞周期调节剂 p21 和 p16 的肾内表达。为了确定肾脏细胞衰老，我们还进行了衰老相关β-半乳糖苷酶（SA-β-gal）和端粒酶逆转录酶（TERT）的免疫染色。依那普利处理显示新生大鼠肾脏中细胞衰老发生了显著改变。在依那普利处理组中，与对照组相比，肾内 p16 和 p21 蛋白表达减少。p21 和 p16 的表达在依那普利处理的大鼠的整个肾皮质和髓质中均减少。依那普利处理的肾脏中 TERT 的免疫反应性也比对照组弱。对照组肾脏的皮质小管中明显有阳性的 SA-β-gal 信号；然而，与对照组相比，依那普利处理组的 SA-β-gal 活性明显降低。在肾发生期间阻断 RAS 可能会破坏发育中大鼠肾脏的生理细胞衰老。
