Abstract
Chronic kidney disease (CKD) is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and treatment is focused on limiting the disease progression. The accumulation of senescent cells has been implicated in the development of kidney fibrosis by limiting tissue rejuvenation and through the secretion of pro-fibrotic and pro-inflammatory mediators termed as the senescence-associated secretory phenotype. The clearance of senescent cells in aging models results in improved kidney function, which shows promise for the options of targeting senescent cells in CKD. There are several approaches for the development of “senotherapies”, the most rigorous of which is the elimination of senescent cells by the so-called senolytic drugs either newly developed or repurposed for off-target effects in terms of selectively inducing apoptosis in senescent cells. Several chemotherapeutics and checkpoint inhibitors currently used in daily oncological practice show senolytic properties. However, the applicability of such senolytic compounds for the treatment of renal diseases has hardly been investigated. A serious concern is that systemic side effects will limit the use of senolytics for kidney fibrosis. Specifically targeting senescent cells and/or targeted drug delivery to the kidney might circumvent these side effects. In this review, we discuss the connection between CKD and senescence, the pharmacological options for targeting senescent cells, and the means to specifically target the kidney.
Highlights
OF RENAL DISEASE AND SENESCENCERenal Disease as a Major Individual and Global BurdenChronic kidney disease (CKD) is defined by the persistent loss of kidney function and currently affects approximately 13.4% of the global population (Hill et al, 2016; Jager and Fraser, 2017)
This review aims to 1) provide a concise description of the pathophysiology of cellular senescence in the kidney and 2) discuss the various potential intervention points within the senescence network
Knockout (KO) of a combination of BCL-W, BCL-XL, and B-cell lymphoma 2 (BCL-2) leads to the reduced viability of senescent cells, showing that these cells depend on theexpression of anti-apoptotic factors to prevent “spontaneous” apoptosis (Chang et al, 2016; Yosef et al, 2016)
Summary
Chronic kidney disease (CKD) is defined by the persistent loss of kidney function and currently affects approximately 13.4% of the global population (Hill et al, 2016; Jager and Fraser, 2017). When DNA injury is irreparable, either apoptosis or a permanent inhibition of cell cycle progression occurs despite growth factor stimulation The latter situation/condition is known as cellular senescence (Campisi and d’Adda di Fagagna, 2007). Knockout (KO) of a combination of BCL-W, BCL-XL, and BCL-2 leads to the reduced viability of senescent cells, showing that these cells depend on the (over)expression of anti-apoptotic factors to prevent “spontaneous” apoptosis (Chang et al, 2016; Yosef et al, 2016). Tied to their dependence on BCL-2 protein family members, senescent cells are reliant on pro-survival pathways involving the p53-p21-serpine and phosphoinositide 3-kinase (PI3K)/ AKT pathways. The reduction of BCL-2 in irradiated fibroblasts is not consistently seen and the expression of pro- and anti-apoptotic proteins may vary depending on the cell type (Zhu et al, 2016), which could explain the observed differences in response to therapies targeting specific apoptotic pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
