Senloytics, dasatinib plus quercetin, reduce kidney inflammation, senescent cell abundance, and injury while restoring geroprotective factors in murine diabetic kidney disease
Abstract
Summary 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 (p16Ink4a), 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…
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