Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by the involvement of multiple organs. Lupus nephritis (LN) is a major risk factor for overall morbidity and mortality in SLE patients. Hence, designing effective drugs is pivotal for treating individuals with LN. Fisetin plays a senolytic role by specifically eliminating senescent cells, inhibiting cell proliferation, and exerting anti-inflammatory, anti-oxidant, and anti-tumorigenic effects. However, limited research has been conducted on the utility and therapeutic mechanisms of fisetin in chronic inflammation. Similarly, whether the effects of fisetin depend on cell type remains unclear. In this study, we found that LN-prone MRL/lpr mice demonstrated accumulation of Ki-67-positive myofibroblasts and p15INK4B-positive senescent tubular epithelial cells (TECs) that highly expressed transforming growth factor β (TGF-β). TGF-β stimulation induced senescence of NRK-52E renal TECs and proliferation of NRK-49F renal fibroblasts, suggesting that TGF-β promotes senescence and proliferation in a cell type-dependent manner, which is inhibited by fisetin treatment in vitro. Furthermore, fisetin treatment in vivo reduced the number of senescent TECs and myofibroblasts, which attenuated kidney fibrosis, reduced senescence-associated secretory phenotype (SASP) expression, and increased TEC proliferation. These data suggest that the effects of fisetin vary depending on the cell type and may have therapeutic effects in complex and diverse LN pathologies.

Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment

“…The senolytic activity of Fisetin, a flavonoid polyphenol, has been discovered during an in vitro screen of different polyphenols and its activity has been confirmed in vivo by analyzing the evolution of senescent cells accumulation in progeroid mice 19 . Since this study, several other publications highlighted the potential interest of Fisetin to treat different diseases related to senescence cells accumulation such as kidney fibrosis 20 or muscular dystrophy 21 . More recently, Fisetin treatment in SARS-CoV-2 infection displayed a significant activity in vivo by eliminating senescent cells and reduced mortality associated with the virus 22 .…”

Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

“…Studies have shown that acute or intermittent treatment of fisetin in both early and old mice can reduce aging markers in multiple tissues, reduce inflammation and oxidative stress, improve tissue homeostasis, and reduce a variety of age-related pathological changes [160]. In vivo studies found that the number of senescent renal tubular epithelial cells and myofibroblasts was significantly reduced after fisetin treatment, thereby alleviating renal fibrosis and reducing SASP expression [161]. A recent study found that fisetin could ameliorate skin aging by selectively removing senescent dermal fibroblasts and inhibiting SASP, suggesting that fisetin may be an effective novel therapeutic agent against skin aging [162].…”

Role of cellular senescence in inflammation and regeneration

“…In addition to age-related diseases, developmental, genetic, and autoimmune diseases are affected by senescent cells regardless of age. Some examples include neurodevelopmental defects [ 86 – 88 ], Duchenne muscular dystrophy (DMD) [ 89 ], and autoimmune diseases [ 90 – 92 ]. Drug use during pregnancy and maternal diabetes are major non-genetic factors in neurodevelopmental defects.…”