Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Aging Cell. 2012 Dec;11(6):1065-73. doi: 10.1111/acel.12008. Epub 2012 Oct 19.
We explored molecular events associated with aging-induced matrix changes in the kidney. C57BL6 mice were studied in youth, middle age, and old age. Albuminuria and serum cystatin C level (an index of glomerular filtration) increased with aging. Renal hypertrophy was evident in middle-aged and old mice and was associated with glomerulomegaly and increase in mesangial fraction occupied by extracellular matrix. Content of collagen types I and III and fibronectin was increased with aging; increment in their mRNA varied with the phase of aging. The content of ZEB1 and ZEB2, collagen type I transcription inhibitors, and their binding to the collagen type Iα2 promoter by ChIP assay also showed age-phase-specific changes. Lack of increase in mRNA and data from polysome assay suggested decreased degradation as a potential mechanism for kidney collagen type I accumulation in the middle-aged mice. These changes occurred with increment in TGFβ mRNA and protein and activation of its SMAD3 pathway; SMAD3 binding to the collagen type Iα2 promoter was also increased. TGFβ-regulated microRNAs (miRs) exhibited selective regulation. The renal cortical content of miR-21 and miR-200c, but not miR-192, miR-200a, or miR-200b, was increased with aging. Increased miR-21 and miR-200c contents were associated with reduced expression of their targets, Sprouty-1 and ZEB2, respectively. These data show that aging is associated with complex molecular events in the kidney that are already evident in the middle age and progress to old age. Age-phase-specific regulation of matrix protein synthesis occurs and involves matrix protein-specific transcriptional and post-transcriptional mechanisms.
我们探讨了与肾脏衰老诱导的基质变化相关的分子事件。我们研究了 C57BL6 小鼠的青年期、中年期和老年期。尿白蛋白和血清胱抑素 C 水平（肾小球滤过的指标）随年龄增长而增加。中年和老年小鼠出现肾肥大，与肾小球增大和细胞外基质占据的系膜区分数增加有关。胶原类型 I 和 III 以及纤维连接蛋白的含量随年龄增长而增加；其 mRNA 的增加随衰老阶段而变化。ZEB1 和 ZEB2 的含量，胶原类型 I 的转录抑制剂，以及它们通过 ChIP 实验与胶原类型 Iα2 启动子的结合也表现出与年龄阶段特异性的变化。mRNA 含量没有增加，多核糖体分析的数据表明，作为中年小鼠肾脏胶原 I 积累的潜在机制，降解减少。这些变化伴随着 TGFβ mRNA 和蛋白的增加以及其 SMAD3 途径的激活而发生；SMAD3 与胶原类型 Iα2 启动子的结合也增加了。TGFβ 调节的 microRNAs（miRs）表现出选择性调节。肾皮质中的 miR-21 和 miR-200c 含量，但不是 miR-192、miR-200a 或 miR-200b，随年龄增长而增加。miR-21 和 miR-200c 含量的增加与它们的靶基因 Sprouty-1 和 ZEB2 的表达减少有关。这些数据表明，衰老与肾脏中的复杂分子事件有关，这些事件在中年时已经很明显，并随着年龄的增长而进展到老年期。基质蛋白合成的年龄阶段特异性调节发生，并涉及基质蛋白特异性的转录和转录后机制。
