Abstract: TH-PO180
Senolytics, Dasatinib Plus Quercetin, Improve Kidney Function and Reduce Inflammation in Murine Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - I
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Bian, Xiaohui, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Snow, Zachary Kayne, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Smith, Anastasia L., Mayo Clinic in Florida, Jacksonville, Florida, United States
- Skaff, Caroline Janet, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Elhusseiny, Khaled Mosaad, Mayo Clinic in Florida, Jacksonville, Florida, United States
- Zhu, Yi, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Tchkonia, Tamara, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Kim, Seo Rin, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Kirkland, James L., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Lerman, Lilach O., Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Hickson, LaTonya J., Mayo Clinic in Florida, Jacksonville, Florida, United States
Group or Team Name
- Mayo Translational and Regenerative Nephrology Research Laboratory
Background
Senolytic agents, dasatinib plus quercetin (D+Q), reduced systemic inflammation, macrophage infiltration, and senescent cell burden in adipose tissue in our pilot study of human participants with diabetic kidney disease (DKD). We hypothesized that D+Q would attenuate kidney injury and inflammation in a murine model of DKD.
Methods
Twelve-week-old male C57BL/6 mice were injected with 50 mg/kg/d STZ i.p. for 5 (+3) consecutive days (Figure). Mice with fasting glucose >250 mg/dL at day 100 were randomized to either D+Q (5 and 50 mg/kg, respectively) or vehicle gavage daily for 5 days and euthanized 20 days later. Kidney injury (Mac-2, KIM-1), inflammation (MCP-1, IL-6, IL-1β, TNFα), profibrotic markers (TGFβ1, fibronectin), cellular senescence (p16), and geroprotective factors (α-Klotho, Sirt-1) were examined by qPCR, and kidney function by serum creatinine. In vitro, we assessed the response to D+Q in renal tubular epithelial cells (HK2) injured by high glucose and TGF-β1.
Results
Oral D+Q improved kidney function and decreased kidney injury, profibrotic factors, and senescence marker p16 vs. vehicle-treated mice. In addition, pro-inflammatory (senescence-associated secretory proteins) kidney makers were reduced following D+Q. Finally, both α-Klotho and Sirt-1 increased in DKD tissue in vivo and HK2 cells in vitro after D+Q.
Conclusion
A “hit and run” treatment with D+Q can attenuate murine DKD injury by altering the inflammatory landscape, reducing senescent cell abundance, and restoring geroprotective factors. D+Q might represent a novel therapeutic strategy in DKD.
Funding
- NIDDK Support