Abstract: FR-PO303
Clearance of P16-Positive Senescent Cells Delays Diabetic Kidney Disease (DKD) by Normalizing Glycolysis and Mitochondrial Metabolic Disorder
Session Information
- Diabetic Kidney Disease: Basic - 1
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Lu, Xiao, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Wu, Jiao, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Agborbesong, Ewud, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Background
Diabetic kidney disease (DKD) is one of the complications of diabetes, which is characterized by kidney damage and abnormal renal energy metabolism. Studies have shown that senescence is associated with the course of DKD. Recently, attention has focused on the effect of purging p16-positive senescent cells in transgenic mice on the increase of mean lifespan. However, whether and how p16 positive senescent cells promote the progression of DKD remain unknown.
Methods
To evaluate the role and mechanisms of p16 positive senescent cells in DKD progression, we established type 1 diabetes model (DM) through injection of streptozotocin in INK-ATTAC transgenic mice, which allowed a removal of p16Ink4a-positive cells upon administration of a drug, AP20187. We treated human renal tubular epithelial cells (HK2) cultured with different concentration of glucose. We also isolated the primary tubular epithelial cells from vehicle and AP treated DM INK-ATTAC mouse kidneys.
Results
We found that the expression of p16 was increased in renal tubular cells in the kidneys of DM mice and DKD patients as well as in HK2 cells cultured in high glucose media, which promoted senescence and elevated senescence-associated secretory phenotypes (SASPs), including TNF-α, IL-6 and IL-1β, in those kidneys and cells as examined with SA-β-gal staining and qRT-PCR analysis. Importantly, we found that clearance of p16-positive cells 1) delayed the progression of DKD as seen by the decrease of serum creatinine and urine microalbumin in DM INK-ATTAC mouse treated with AP20187, 2) alleviated kidney injury in diabetic mice through Rb-CDK4 pathway and the decrease of SASPs, and 3) restored ATP content, decreased the expression of the key glycolytic enzymes, and improved the metabolic reprogramming in DM INK-ATTAC mouse kidneys. In addition, clearance of p16-positive cells normalized the expression of the genes involved in mitochondrial metabolism through AMPK and mTOR pathway, suggesting that p16 positive senescent cells also played an important role in renal mitochondrial metabolic disorder in DKD.
Conclusion
Our study indicates that p16 positive senescent cells plays an important role in the progression of DKD, and their clearance delays the progression of DKD through normalizing glycolysis and mitochondrial metabolic disorder, which is a novel therapeutic target for DKD.