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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Kidney Injury / genetics*
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Acute Kidney Injury / metabolism
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Acute Kidney Injury / pathology
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Acute Kidney Injury / prevention & control
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Animals
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Cell Line, Transformed
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Cell Proliferation
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Cellular Senescence
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Coculture Techniques
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Culture Media, Conditioned / pharmacology
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Cyclin-Dependent Kinase Inhibitor p16 / deficiency
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Cyclin-Dependent Kinase Inhibitor p16 / genetics*
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Epithelial-Mesenchymal Transition / genetics*
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Gene Expression Regulation
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Humans
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Kidney Tubules, Proximal / metabolism
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Kidney Tubules, Proximal / pathology
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Mice
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Mice, Knockout
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Nephritis, Interstitial / genetics*
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Nephritis, Interstitial / metabolism
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Nephritis, Interstitial / pathology
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Nephritis, Interstitial / prevention & control
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Polycomb Repressive Complex 1 / antagonists & inhibitors
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Polycomb Repressive Complex 1 / deficiency
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Polycomb Repressive Complex 1 / genetics*
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Polycomb Repressive Complex 1 / metabolism
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Smad Proteins / genetics
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Smad Proteins / metabolism
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
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Transforming Growth Factor beta1 / pharmacology
Substances
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BMI1 protein, human
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Bmi1 protein, mouse
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Cdkn2a protein, mouse
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Culture Media, Conditioned
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Cyclin-Dependent Kinase Inhibitor p16
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NF-kappa B
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Smad Proteins
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Transforming Growth Factor beta1
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Polycomb Repressive Complex 1