Abstract: SA-PO115
Transplanted Senescent Renal Tubular-Like Cells Induce Renal Microvascular Injury
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Kim, Seo Rin, Mayo clinic, Rochester, United States
- Jiang, Kai, Mayo clinic, Rochester, Minnesota, United States
- Ferguson, Christopher M., Mayo clinic, Rochester, Minnesota, United States
- Tang, Hui, Mayo clinic, Rochester, Minnesota, United States
- Chen, Xiaojun, Mayo clinic, Rochester, Minnesota, United States
- Zhu, Xiang yang, Mayo clinic, Rochester, Minnesota, United States
- Hickson, LaTonya J., Mayo clinic, Rochester, Minnesota, United States
- Tchkonia, Tamara, Mayo Clinic, Rochester, Minnesota, United States
- Kirkland, James L., Mayo Clinic, Rochester, Minnesota, United States
- Lerman, Lilach O., Mayo clinic, Rochester, Minnesota, United States
Background
Cellular senescence is characterized by a senescence-associated secretory phenotype (SASP), which reinforces senescence and exerts noxious effects on adjacent cells. Recent studies suggest that transplanting small numbers of senescent cells suffices to provoke tissue inflammation. Several models of kidney disease show increased prevalence of senescent renal cells. We hypothesized that senescent cells can directly augment renal injury.
Methods
Cellular senescence was induced in primary tubular-like cells acquired from pig kidneys by 10Gy of cesium radiation, and 3 weeks later cells were characterized for senescence and SASP markers. Control (CON) or senescent (SEN) renal tubular-like cells were pre-labeled and injected intra-aorta to C57BL/6J mice. Four weeks later, renal oxygenation was studied using magnetic resonance imaging, and function by plasma creatinine level. Renal markers of SASP, fibrosis, and microvascular density were evaluated.
Results
Per flow cytometry, 80-99% renal tubular-like cells were senescent after irradiation. They showed increased mRNA of senescence and SASP markers, SA-ß-gal staining, and cytokines levels secreted in conditioned-medium. Four weeks after injection, cells were detected engrafted in the kidneys with no evidence for rejection. Plasma creatinine and renal tissue hypoxia tended to increase in SEN compared to CON. SEN kidneys were more fibrotic, with fewer CD31+ endothelial cells, and showed upregulation of IL-6 gene expression.
Conclusion
Senescent renal tubular-like cells directly induce renal inflammation, fibrosis, microvascular loss, and hypoxia. These observations suggest a role for cellular senescence in the pathogenesis of kidney injury, and support development of senolytic therapy.
Funding
- NIDDK Support