Senolytics, dasatanib plus quercetin, reduce kidney inflammation, senescent cell abundance, and injury while restoring geroprotective factors in murine diabetic kidney disease.

Abstract

BACKGROUND: Maladaptive inflammation and cellular senescence contribute to diabetic kidney disease (DKD) pathogenesis and represent important therapeutic targets. Senolytic agents selectively remove senescent cells and reduce inflammation-associated tissue damage. In our pilot clinical trial in patients with DKD, the senolytic combination dasatinib plus quercetin (D + Q) reduced systemic inflammation, senescent cell abundance, and macrophage infiltration in fat. However, D + Q senotherapeutic effects on diabetic kidney injury, senescence, inflammation, and geroprotective factors have not been established. METHODS: Diabetes mellitus was induced with intraperitoneal streptozotocin in male C57BL/6J mice, followed by a 5-day oral gavage regimen of either D + Q (5 and 50 mg/kg, respectively) or vehicle. Kidney function and markers of injury, fibrosis, inflammation, cellular senescence, and geroprotective factors were measured. In vitro studies examined reparative effects of D + Q in high glucose-treated human renal tubular epithelial cells (HK2), endothelial cells (HUVECs), and U937-derived macrophages. FINDINGS: D + Q improved kidney function and reduced markers of kidney injury (glomerular and tubular), fibrosis, senescence (p16), macrophage- and senescence-associated inflammation (versus diabetic controls) without altering glucose levels. Additionally, geroprotective factors (α-Klotho, Sirtuin-1) increased. D + Q treatment in vitro reduced high glucose-induced senescence and inflammation (NF-κB) in HK2, HUVECs, and macrophages. INTERPRETATION: A "hit-and-run" senolytic treatment with D + Q improved kidney function and mitigated murine DKD by modulating the inflammatory landscape, reducing senescent cell abundance, and restoring geroprotective factors. Taken together, the beneficial effects in kidneys of mice and prior systemic effects in humans, support the rationale for further clinical investigations applying D + Q to enhance healthspan in individuals with DKD. FUNDING: This research was supported by National Institutes of Health (NIH): [DK123492, DK109134, and AG076537 (LJH); DK120292 and HL158691 (LOL); AG087387 (YZ); R37AG013925 (TT and JLK)]; NIDDK Diabetes Complications Consortium [DK115255, DK076169 (LJH)]; Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery (LJH); TT and JLK are supported by a grant from the Hevolution Foundation (HF-GRO-23-1199148-3), Cedars-Sinai Medical Center, the Connor Fund, and Robert J. and Theresa W. Ryan.