1,25-Dihydroxyvitamin D deficiency accelerates male reproductive senescence in aging mice and 1,25(OH)2D3 alleviates oxidative stress via NF-?B/SOD
1,25-Dihydroxyvitamin D deficiency accelerates male reproductive senescence in aging mice and 1,25(OH)2D3 alleviates oxidative stress via NF-?B/SOD
复制标题
1,25-二羟基维生素 D 缺乏会加速衰老小鼠的雄性生殖衰老，1,25(OH)2D3 通过 NF-κB/SOD 减轻氧化应激
DOI：
10.1152/ajpendo.00531.2020
复制
发表时间：
2021-04-01
影响因子：
5.1
通讯作者：
Sun, Weiwei
中科院分区：
文献类型：
--
作者：
He, Jialing;Wang, Hui;Sun, Weiwei
1,25(OH)2D3已被证明对人类或动物的男性生殖系统有直接作用。随着年龄的增长，肾脏中1,25(OH)2D3的合成明显下降，补充维生素D可以缓解男性生殖衰老的表现。因此，1,25(OH)2D3与男性生殖衰老的关系有待进一步研究。为了确定1,25(OH)2D3缺乏是否会加速衰老小鼠的雄性生殖衰老，野生型和1a（OH）酶-/-雄性小鼠在断奶后饲喂拯救饲料，并在12？18岁。我们证明1,25(OH)2D3缺乏加速了男性生殖衰老，表现为生育效率和性腺激素水平降低，细胞增殖减少，细胞凋亡增加，细胞衰老和衰老相关分泌表型（SASP）。我们证实，在1a（OH）酶-/-小鼠中检测到的氧化应激和DNA损伤的增加导致生殖系统的生殖衰老加速，因为外源性抗氧化剂吡咯喹啉醌（PQQ）补充可以在很大程度上挽救生殖衰老表型。我们进一步验证了1,25(OH)2D3对衰老野生型小鼠和衰老间质细胞的抗氧化作用，通过1,25(OH)2D3或对照剂处理18岁野生型雄性小鼠或TM3细胞。我们利用RNA-Seq技术评估了分组衰老TM3细胞之间的基因表达差异，证实了1,25(OH)2D3通过作用于NF?B/SOD发挥抗氧化作用。本研究提示，1,25(OH)2D3缺乏通过增加氧化应激加速衰老小鼠雄性生殖衰老，而1,25(OH)2D3通过NF-？B/SOD信号通路。基于本研究，我们提出1,25(OH)2D3可以延缓男性生殖衰老，并提出1,25(OH)2D3调节NF-？B发挥抗氧化作用。因此，1,25(OH)2D3可能是一种有效的维持生育力和延缓男性生殖衰老的药物。
1,25(OH)2D3 has been demonstrated to exert direct actions on male reproductive system in humans or in animals. With age, renal synthesis of 1,25(OH)2D3 declines significantly, and vitamin D supplementation has been found to alleviate the manifestations of male reproductive aging. Therefore, the relationship between 1,25(OH)2D3 and male reproductive aging needs further study. To determine whether 1,25(OH)2D3 deficiency accelerates male reproductive senescence in aging mice, wild-type and 1a(OH)ase-/- male mice fed a rescue diet after weaning, and the reproductive phenotypes were evaluated at 12?18 mo of age. We demonstrated that 1,25(OH)2D3 deficiency accelerated male reproductive senescence, representing lower fertility efficiency and gonadal hormone levels, reducing cell proliferation, and increasing cell apoptosis, cellular senescence, and the senescence-associated secretory phenotype (SASP). We confirmed that the increased oxidative stress and DNA damage detected in 1a(OH)ase-/- mice resulted in accelerated reproductive senescence in reproductive system, since exogenous antioxidant pyrroloquinoline quinone (PQQ) supplementation could largely rescue reproductive aging phenotype. We further validated the antioxidant effect of 1,25(OH)2D3 in aging wild-type mice and senescent Leydig cells by treated 18-mo-old wild-type male mice or TM3 cells with 1,25(OH)2D3 or vehicle. We assessed the differential gene expression between grouped senescent TM3 cells using RNA-Seq and verified 1,25(OH)2D3 exerted an antioxidant role by acting NF?B/SOD. This study suggests that 1,25(OH)2D3 deficiency accelerates male reproductive senescence in aging mice by increasing oxidative stress and 1,25(OH)2D3 plays a role in alleviating oxidative stress via NF-?B/SOD signaling pathway. NEW & NOTEWORTHY Based on this studies, we propose that 1,25(OH)2D3 can delay male reproductive aging, and we also propose that 1,25(OH)2D3 regulates NF-?B to exert antioxidant effect. Therefore, by targeting a fundamental aging mechanism, 1,25(OH)2D3 may be an effective agent in maintaining fertility and postponing male reproductive senescence.