INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction
Open accessAbstract
The INK4a proteins p16(INK4a) and p19(ARF) regulate cell cycle arrest and senescence. However, the role of these proteins in controlling these processes in the normal kidney and following injury is unknown. We performed unilateral ureteral obstruction (UUO) to induce fibrosis in 2- to 3-mo-old wild-type (WT) C57/B6 and INK4a knockout mice. By quantitative RT-PCR, p16(INK4a) levels were increased sixfold in WT mice 7 days after UUO and p19(ARF) remained undetectable. Kidney sections were examined to determine levels and localization of p16(INK4a), apoptosis, fibrosis, and senescent cells. INK4a knockout mice displayed mesangial cell proliferation, increased matrix deposition, and myofibroblast differentiation under normal conditions. Following UUO, INK4a knockout mice displayed 10-fold increased tubular and interstitial cell proliferation, 75% decreased collecting duct apoptosis, 2-fold greater collagen and fibronectin deposition, and no cell senescence by senescence-associated β-galactosidase staining compared with WT mice. Both INK4a knockout mesangial cells and kidney lysates from knockout mice following injury showed elevated levels of IL-6 by ELISA compared with WT samples. INK4a knockout epithelial cell cultures displayed increased mesenchymal cell markers when exposed to transforming growth factor-β. These results confirm that p16(INK4a) controls cell proliferation and matrix production and mitigates fibrosis following injury and suggest that the mechanism involves a role in limiting inflammation and cell proliferation.
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Similar antifibrotic effects of senescent cells have been observed in the kidneys, liver and lungs in mouse models.
“similar antifibrotic effects of senescent cells have been observed in the kidneys, liver and lungs in mouse models 10-12”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [11]
Acute senescence has beneficial effects and contributes to antifibrotic mechanisms in murine models of unilateral ureteral obstruction, which leads to tubular injury and subsequent renal fibrosis.
“For example, acute senescence has been observed to have beneficial effects and to contribute to antifibrotic mechanisms in murine models of unilateral ureteral obstruction, which leads to tubular injury and subsequent renal fibrosis.”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [103]
In INK4-knockout mice subjected to unilateral ureteral obstruction, p16INK4A has an important role in reducing inflammation and cell proliferation.
“Studies in INK4-knockout mice subjected to unilateral ureteral obstruction showed that p16INK4A has an important role in reducing inflammation and cell proliferation.103”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [103]
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- Authors
- Wolstein, J. M., Lee, D. H., Michaud, J., Buot, V., Stefanchik, B., & Plotkin, M. D.
- Affiliations
- New York Medical College (US)
- Corresponding author
- Plotkin, Matthew D.
- ORCID
- Plotkin, Matthew D.
- Venue
- American Journal of Physiology-Renal Physiology
- Publisher
- American Physiological Society
- Published
- 2010-12
- Volume
- 299
- Issue
- 6
- Pages
- F1486-F1495
- ISSN
- 1522-1466 (ISSN-L)
- 1931-857X
- PMC
- PMC3006303
- OpenAlex
- W1982445841
- Cited by
- 83
- References
- 27
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 4 · 2022: 6 · 2021: 14 · 2020: 15 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 4 · 2014: 4 · 2013: 2 · 2012: 2
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Renal Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k08dk067881-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 067881)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- INK4A, p16INK4a, p19ARF, renal fibrosis, unilateral ureteral obstruction, kidney injury, cell cycle arrest, cellular senescence, apoptosis, mesangial cell proliferation, myofibroblast differentiation, collagen deposition, fibronectin, interleukin-6, inflammation, TGF-beta, mesenchymal transition, collecting duct
- MeSH terms
- Animals, Fibrosis, Kidney, Male, Ureteral Obstruction, Cellular Senescence, Apoptosis, Mice, Knockout, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice
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