Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease

Abstract

Chronic kidney disease (CKD) is increasingly being accepted as a type of renal ageing. The kidney undergoes age-related alterations in both structure and function. To date, a comprehensive analysis of cellular senescence and senescence-associated secretory phenotype (SASP) in CKD is lacking. Hence, this review mainly discusses the relationship between the two phenomena to show the striking similarities between SASP and CKD-associated secretory phenotype (CASP). It has been reported that replicative senescence, stress-induced premature ageing, and epigenetic abnormalities participate in the occurrence and development of CKD. Genomic damage and external environmental stimuli cause increased levels of oxidative stress and a chronic inflammatory state as a result of irreversible cell cycle arrest and low doses of SASP. Similar to SASP, CASP factors activate tissue repair by multiple mechanisms. Once tissue repair fails, the accumulated SASP or CASP species aggravate DNA damage response (DDR) and cause the senescent cells to secrete more SASP factors, accelerating the process of cellular ageing and eventually leading to various ageing-related changes. It is concluded that cellular senescence and SASP participate in the pathological process of CKD, and correspondingly CKD accelerated the progression of cell senescence and the secretion of SASP. These results will facilitate the integration of these mechanisms into the care and management of CKD and other age-related diseases.

Keywords: CKD-associated secretory phenotype; cellular senescence; chronic kidney disease; senescence-associated secretory phenotype.

Figure 1. Cellular aging and SASP in CKD

Many factors including urinary toxins, infections, dialysis treatment, excessive activation of RAS, can cause and increase telomere shorten, the levels of oxidative stress, and abnormal epigenetic modification, resulting in cell cycle arrest and senescence related morphological changes. Sustained DNA damage response and/or the increased level of ROS directly or indirectly activate transcription factor NF-κB and C/EBP-β and further cause the secretion of SASP. SASP not only can recruit immune cells to clear antigens and the damage cells, but also can launch tissue repair by activating cellular proliferation and differentiation of progenitor cells, stem cells, or the legacy of kidney inherent cell. Once the tissue repair fails, gathered SASP will aggravate DNA damage response and cause the senescent cells to secrete more SASP, accelerating the process of cellular aging and eventually leading to ESRD and other aging-related changes. RAS: Renin-angiotensin system; ROS: Reactive oxygen species; MAPK: Mitogen-activated protein kinase; DDR: DNA damage response; NF-κB: Nuclear transcription factor; C/EBP-β: CCAAT enhancer binding protein β; SASP: Senescence-associated secretory phenotype; ESRD, End-stage renal disease.