P16 (INK4a) Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency.
P16 (INK4a) Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency.
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P16(INK4a) 缺失可改善 Bmi-1 缺陷的应激诱导过早衰老模型中的肾小管间质损伤
DOI：
10.1038/s41598-017-06868-8
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发表时间：
2017-08-08
影响因子：
4.6
通讯作者：
Miao D
中科院分区：
文献类型：
--
作者：
Jin J;Tao J;Gu X;Yu Z;Wang R;Zuo G;Li Q;Lv X;Miao D
为了确定 p16 INK4a 缺失是否通过抑制 Bmi-1 缺陷 (Bmi-1 −/−) 小鼠的衰老相关分泌表型 (SASP) 来改善肾小管间质损伤，比较了 5 周龄 Bmi-1 和 p16 INK4a 双敲除小鼠以及 Bmi-1 −/− 和野生型小鼠的肾脏表型 老鼠。对三组的第五代肾间质成纤维细胞（RIF）进行衰老和增殖分析。在Bmi-1敲低的人肾近端肾小管上皮（HK2）细胞中检查Bmi-1缺乏对上皮间质转化（EMT）的影响，该细胞用来自上述三组小鼠第五代肾间质成纤维细胞（RIF）的浓缩条件培养基（CM）或外源TGF-β1处理。 Our results demonstrated that p16 INK4a deletion largely rescued renal aging phenotypes caused by Bmi-1 deficiency, including impaired renal structure and function, decreased proliferation, increased apoptosis, senescence and SASP, DNA damage, NF-κB and TGF-β1/Smad signal activation, inflammatory cell infiltration, and tubulointerstitial fibrosis and tubular atrophy. P16 INK4a 缺失还促进 RIF 的增殖、减少衰老和 SASP，并随后抑制 Bmi-1 敲低 HK2 细胞的 EMT。 TGF-β1进一步诱导Bmi-1敲低的HK2细胞的EMT。因此，p16 INK4a 阳性衰老细胞将成为预防肾小管间质损伤的治疗靶点。
To determine whether p16 INK4a deletion ameliorated renal tubulointerstitial injury by inhibiting a senescence-associated secretory phenotype (SASP) in Bmi-1-deficient (Bmi-1 −/−) mice, renal phenotypes were compared among 5-week-old Bmi-1 and p16 INK4a double-knockout, and Bmi-1 −/− and wild-type mice. Fifth-passage renal interstitial fibroblasts (RIFs) from the three groups were analyzed for senescence and proliferation. The effect of Bmi-1 deficiency on epithelial-to-mesenchymal transition (EMT) was examined in Bmi-1-knockdown human renal proximal tubular epithelial (HK2) cells, which were treated with concentrated conditioned medium (CM) from the fifth-passage renal interstitial fibroblasts (RIFs) of above three group mice or with exogenous TGF-β1. Our results demonstrated that p16 INK4a deletion largely rescued renal aging phenotypes caused by Bmi-1 deficiency, including impaired renal structure and function, decreased proliferation, increased apoptosis, senescence and SASP, DNA damage, NF-κB and TGF-β1/Smad signal activation, inflammatory cell infiltration, and tubulointerstitial fibrosis and tubular atrophy. P16 INK4a deletion also promoted proliferation, reduced senescence and SASP of RIFs and subsequently inhibited EMT of Bmi-1-knockdown HK2 cells. TGF-β1 further induced the EMT of Bmi-1-knockdown HK2 cells. Thus, p16 INK4a positive senescent cells would be a therapeutic target for preventing renal tubulointerstitial injury.
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影响因子：
6
作者：
Christian F;Smith EL;Carmody RJ
通讯作者：
Carmody RJ
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
多普勒参数与肾脏病理学的相关性：一项针对 992 名患者的研究
影响因子：
2.7
作者：
Chen Q;He F;Feng X;Luo Z;Zhang J;Zhang L;Wang Y;Tong J
通讯作者：
Tong J
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J