Senolytics, Dasatinib Plus Quercetin, Improve Kidney Function and Reduce Inflammation in Murine Diabetic Kidney Disease

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(definition) (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. Conclusions: 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