Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

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.

Deciphering the Efficacy and Mechanisms of Chinese Herbal Medicine for Diabetic Kidney Disease by Integrating Web-Based Biochemical Databases and Real-World Clinical Data: Retrospective Cohort Study

“…It is reported that proximal tubular cells arrested in the G2/M phase after an injury are responsible for the fibrotic response, which leads to CKD [83,84,86]. Hence, helping cells abrogate the G2/M arrest and preventing profibrotic growth factor release are new strategies for avoiding renal fibrosis [81,87]. According to our results, several pathways related to the cell cycle may be covered by CHM clusters, especially in pathways related to G2/M checkpoints.…”

“…A previous study found that specific CHMs are involved in DKD-related modulation of microRNA [79]. Besides, the importance of cell cycle arrest in treating CKD seems to be increasing in recent years [80][81][82][83][84]. Cell division involves the following four phases: G0-G1, S, G2, and M. To repair the injured tissue ultimately, DNA is replicated and divided in the process of the cell cycle.…”

Rodent studies of developmental programming and ageing mechanisms

“…2 These cellular and molecular systems bear several similarities to pathways that are modified by programming such as decreased apoptosis and proteasome function 3 and fibrosis. 4 Thus, it is not surprising their interactions occur between developmental programming and ageing as will be described here. In this review, we will first address some of the fundamental principles of programming and ageing interactions.…”

“…Another review considers the seven pillars of ageing as metabolism, macromolecular damage, epigenetics inflammation, stem cells and regeneration, proteostasis and adaptation to stress 2 . These cellular and molecular systems bear several similarities to pathways that are modified by programming such as decreased apoptosis and proteasome function 3 and fibrosis 4 . Thus, it is not surprising their interactions occur between developmental programming and ageing as will be described here.…”

Chloride channel accessory 1 integrates chloride channel activity and mTORC1 in aging‐related kidney injury

“…SASP has been linked to mTOR activation (Herranz et al, 2015). SASP involves the secretion of pro-fibrotic factors that promote kidney fibrosis (Xu et al, 2020). Wnt9-TGFβ1 pathway has been shown to be involved in this process (Luo et al, 2018).…”