P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency

Abstract 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 wi...

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Autores principales:	Jianliang Jin, Jianguo Tao, Xin Gu, Zhenzhen Yu, Rong Wang, Guoping Zuo, Qing Li, Xianhui Lv, Dengshun Miao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4c64dd3346f74c08ba57765ffa2e2944
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spelling	oai:doaj.org-article:4c64dd3346f74c08ba57765ffa2e29442021-12-02T11:52:56ZP16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency10.1038/s41598-017-06868-82045-2322https://doaj.org/article/4c64dd3346f74c08ba57765ffa2e29442017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06868-8https://doaj.org/toc/2045-2322Abstract 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.Jianliang JinJianguo TaoXin GuZhenzhen YuRong WangGuoping ZuoQing LiXianhui LvDengshun MiaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jianliang Jin Jianguo Tao Xin Gu Zhenzhen Yu Rong Wang Guoping Zuo Qing Li Xianhui Lv Dengshun Miao P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency
description	Abstract 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.
format	article
author	Jianliang Jin Jianguo Tao Xin Gu Zhenzhen Yu Rong Wang Guoping Zuo Qing Li Xianhui Lv Dengshun Miao
author_facet	Jianliang Jin Jianguo Tao Xin Gu Zhenzhen Yu Rong Wang Guoping Zuo Qing Li Xianhui Lv Dengshun Miao
author_sort	Jianliang Jin
title	P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency
title_short	P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency
title_full	P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency
title_fullStr	P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency
title_full_unstemmed	P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency
title_sort	p16 ink4a deletion ameliorated renal tubulointerstitial injury in a stress-induced premature senescence model of bmi-1 deficiency
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4c64dd3346f74c08ba57765ffa2e2944
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P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency

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