Abstract
Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed as a state of accelerated and premature aging. Aging kidney and CKD share many common characteristic features with increased cellular senescence, a conserved program characterized by an irreversible cell cycle arrest with altered transcriptome and secretome. While developmental senescence and acute senescence may positively contribute to the fine-tuning of embryogenesis and injury repair, chronic senescence, when unresolved promptly, plays a crucial role in kidney fibrogenesis and CKD progression. Senescent cells elicit their fibrogenic actions primarily by secreting an assortment of inflammatory and profibrotic factors known as the senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent cells could be a promising new target for therapeutic intervention known as senotherapy, which includes depleting senescent cells, modulating SASP and restoration of senescence inhibitors. In this review, we discuss current understanding of the role and mechanism of cellular senescence in kidney fibrosis. We also highlight potential options of targeting senescent cells for the treatment of CKD.
Highlights
Chronic kidney disease (CKD) afflicts more than 10% population and is becoming a major public health problem worldwide (Denic et al, 2016; Yang et al, 2020)
In a study with podocyte-specific Sirtuin 1 (SIRT1) knockdown mice, aged mice display more accumulation of senescent cells and severer sclerosis in glomerulus compared to controls, and this effect is mediated by an increased acetylation of FOXO3, FOXO4, nuclear factor κ-B (NF-κB) and PGC-1α (Chuang et al, 2017)
As senescence plays a crucial role in aging and disease, senescent cells have emerged as promising new target for therapeutic intervention known as senotherapy
Summary
Chronic kidney disease (CKD) afflicts more than 10% population and is becoming a major public health problem worldwide (Denic et al, 2016; Yang et al, 2020). The costs for managing CKD patients are staggering, which imposes tremendous burdens to the afflicted individuals, families and societies, respectively (Wang et al, 2016). Current therapies include lifestyle and dietary modifications, blood pressure management by blocking the renin angiotensin aldosterone system (RAAS), and glycemic control (Breyer and Susztak, 2016; Kalantar-Zadeh and Fouque, 2017; Ruiz-Ortega et al, 2020). These remedies at best only slow, but not completely halt, CKD progression, and they are often ineffective and possess adverse side effects. It is paramount and urgent to elucidate the patho-mechanisms of CKD and to develop new therapeutic strategies
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