Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy
Open accessAbstract
Aims Kidney cells in patients with diabetic nephropathy are reported to be senescent. However, the mechanisms that regulate cellular senescence in the diabetic kidney are still unknown. In the present study, we evaluated the contribution of high glucose to renal cell senescence in streptozotocin (STZ)-induced diabetic mice.Methods Non-diabetic and streptozotocin (STZ, 10mgkg(-1)day(-1) for 7days, i.p.)-induced type 1 diabetic C57BL/6J mice and cultured human proximal tubular cells were used in this study.Results Hyperglycemia dramatically increased the renal expression of p21 but not other CDK inhibitors such as p16 and p27 at 4weeks after STZ injection. These changes were accompanied by an increase in senescence-associated β-galactosidase staining in tubular epithelial cells. Administration of insulin at doses that maintained normoglycemia or mild hypoglycemia suppressed the changes induced by STZ. Insulin did not affect the senescent markers in non-diabetic mice. Exposure of cultured human proximal tubular cells to 25mmol/L, but not 8mmol/L, glucose medium increased the expression of senescence markers, which was suppressed by knock-down of p21 or sodium glucose cotransporter (SGLT) 2.Conclusions These results suggest that hyperglycemia causes tubular senescence via a SGLT2- and p21-dependent pathway in the type 1 diabetic kidney.
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Senescent cells are observed in kidneys of mouse models of acute kidney injury, diabetic nephropathy, glomerulonephropathy, chronic kidney disease and chronic ischaemic renal injury.
“Senescent cells are also observed in kidneys of mouse models of acute kidney injury, diabetic nephropathy, glomerulonephropathy, chronic kidney disease and chronic ischaemic renal injury140,144–150.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [146]
Experimental — accuracy not yet measuredCellular senescence can be a consequence of replicative exhaustion (telomere dependent) and exposure to cardiovascular risk factors (stress-induced).
“As depicted in Figure 3, cellular senescence can be a consequence of two processes which may run in parallel and are intertwined. The first is replicative exhaustion resulting from chronological age or intense proliferation (telomere dependent)20,124,125 and the latter is exposure to cardiovascular risk factors (stress-induced).13–18”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [18]
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- Authors
- Kitada, K., Nakano, D., Ohsaki, H., Hitomi, H., Minamino, T., Yatabe, J., Felder, R. A., Mori, H., Masaki, T., Kobori, H., & Nishiyama, A.
- Affiliations
- Kagawa University (JP)
- Ehime Prefectural University of Health Science (JP)
- Niigata University (JP)
- Fukushima Medical University (JP)
- University of Virginia (US)
- Corresponding author
- Kitada, Kento
- ORCID
- Venue
- Journal of Diabetes and its Complications
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 28
- Issue
- 5
- Pages
- 604-611
- ISSN
- 0891-6632 (ISSN-L)
- 1056-8727
- PMC
- PMC4153757
- OpenAlex
- W2007248715
- Cited by
- 151
- References
- 43
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 18 · 2023: 9 · 2022: 14 · 2021: 23 · 2020: 15 · 2019: 15 · 2018: 10 · 2017: 9 · 2016: 5 · 2015: 7 · 2014: 3
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Diabetes and its Complications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (24390195, 25670382)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072408)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- hyperglycemia, cellular senescence, diabetic nephropathy, SGLT2, p21, proximal tubular epithelial cells, type 1 diabetes, insulin, senescence-associated β-galactosidase, cyclin-dependent kinase inhibitors, streptozotocin-induced diabetes, high glucose
- MeSH terms
- Animals, Cells, Cultured, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetic Nephropathies, Hyperglycemia, Kidney Tubules, Proximal, Male, Mice, Inbred C57BL, Streptozocin, Signal Transduction, Cellular Senescence, Disease Progression, Cyclin-Dependent Kinase Inhibitor p21, Sodium-Glucose Transporter 2, Mice
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