Changes in the tight junctions of the testis during aging: Role of the p38 MAPK/MMP9 pathway and autophagy in Sertoli cells
Changes in the tight junctions of the testis during aging: Role of the p38 MAPK/MMP9 pathway and autophagy in Sertoli cells
复制标题
衰老过程中睾丸紧密连接的变化：p38 MAPK/MMP9 通路和支持细胞自噬的作用
DOI：
10.1016/j.exger.2022.111729
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发表时间：
2022-02-08
影响因子：
3.9
通讯作者：
Zhao, Haixia
中科院分区：
文献类型：
--
作者：
Ma, Qiongyan;You, Xu;Zhao, Haixia
睾丸支持细胞紧密连接（TJ）功能受损、自噬和p38丝裂原活化蛋白激酶（MAPK）/基质金属蛋白酶9（MMP 9）信号通路激活可导致生精障碍。然而，目前尚不清楚是否减少TJ屏障功能和自噬和激活的p38 MAPK/MMP 9通路在支持细胞与年龄相关的睾丸功能障碍密切相关。因此，我们使用6个月、12个月、18个月和24个月大的Sprague-Dawley大鼠评价了支持细胞的这些变化。结果表明，随着年龄的增长，睾丸形态逐渐退化，表现为脱落的生殖细胞增多，曲细精管直径和曲细精上皮高度减小，精原细胞、初级精母细胞和精子细胞数量减少。此外，由相邻的支持细胞形成的TJ逐渐被破坏，伴随着异常的超微结构和TJ蛋白的表达减少zonula occludens-1（ZO-1），occludin和claudin-11与老化。此外，支持细胞和睾丸中磷酸化p38 MAPK和MMP-9的表达逐渐增加，而与MMP-9共定位的occludin的表达逐渐减少。同时，自噬水平也逐渐降低，包括支持细胞自噬空泡形成减少，轻链3（LC 3）和自噬相关蛋白5（Atg 5）表达减弱。总之，我们的研究结果表明，老化导致受损的TJ屏障功能和曲细精管的退化。其机制可能与p38 MAPK/MMP 9通路的激活和Sertoli细胞自噬的失活有关。
Impaired tight junction (TJ) function and autophagy and the activated p38 mitogen-activated protein kinase (MAPK)/matrix metalloproteinase 9 (MMP9) pathway in Sertoli cells cause spermatogenic disorders. However, it is unclear whether reduced TJ barrier function and autophagy and the activated p38 MAPK/MMP9 pathway in Sertoli cells are closely associated with age-related testicular dysfunction. Thus, we evaluated these changes in Sertoli cells using 6-, 12-, 18-, and 24-month-old Sprague-Dawley rats. The results showed that testicular morphology gradually degenerated, as evidenced by increased exfoliated germ cells, decreased seminiferous tubule diameter and seminiferous epithelium height, and reduced the numbers of spermatogonia, primary spermatocytes and spermatids during the process of aging. In addition, the TJs formed by adjacent Sertoli cells were progressively destroyed accompanied by an abnormal ultrastructure and decreased expression of the TJ proteins zonula occludens-1 (ZO-1), occludin, and claudin-11 with aging. Furthermore, the expression of phosphorylated p38MAPK and MMP-9 in Sertoli cells and testis gradually increased, and the expression of occludin co-localizated with MMP-9 progressively decreased. Meanwhile, autophagy levels also gradually decreased, including decreased autophagic vacuole formation and weak expression of light chain 3 (LC3) and autophagy-related 5 (Atg5) in Sertoli cells. Taken together, our results indicate that aging causes impaired TJ barrier function and degeneration of seminiferous tubules. The mechanism might be related to the activated p38MAPK/MMP9 pathway and inactivated autophagy in Sertoli cells.