Is cellular senescence important in pediatric kidney disease?

Abstract

Somatic cellular senescence (SCS) describes the limited ability of cells to divide. Normally, SCS is associated with physiological aging, but evidence suggests that it may play a role in disease progression, even in young patients. Stressors such as acute injury or chronic inflammation may induce SCS, which in turn exhausts organ regenerative potential. This review summarizes what is known about SCS in the kidney with aging and disease. As most patients with chronic kidney disease (CKD) also develop cardiovascular complications, a second focus of this review deals with the role of SCS in cardiovascular disease. Also, as SCS seems to accelerate CKD and cardiovascular disease progression, developing strategies for new treatment options that overcome SCS or protect a patient from it represents an exciting challenge.

Arterial “inflammaging” drives vascular calcification in children on dialysis

“…While studies have shown that oxidative DNA damage and the senescence markers p16 and p21 are elevated in atherosclerotic plaque and adult vessels from CKD patients, 11,29,30 this is the first study to show increased levels of these markers in vessels from young children, who are free of confounding factors including atherosclerosis, providing compelling evidence that the vascular pathology observed in these patients is closely associated with premature aging. 31,32 Our data suggest that oxidative DNA damage accrual begins in predialysis CKD5, as levels of 8-oxo-dG and p21 were significantly elevated at this stage, but is accelerated in the dialysis milieu leading to unrepaired DNA damage and stress-induced premature senescence a hallmark of which is p16 accumulation. 29,31…”

“…31,32 Our data suggest that oxidative DNA damage accrual begins in predialysis CKD5, as levels of 8-oxo-dG and p21 were significantly elevated at this stage, but is accelerated in the dialysis milieu leading to unrepaired DNA damage and stress-induced premature senescence a hallmark of which is p16 accumulation. 29,31…”

New Insights on Molecular Mechanisms of Renal Aging

“…oxidative stress) may cause accelerated telomere attrition (28) or directly damage DNA, leading to the induction of the DNA damage response via ATM/ATR and p53 (29). Another possibility for how p53 can be activated in a stress‐dependent manner is p19 ARF induction (or the human equivalent p14 ARF ), which binds to mouse double minute 2 (MDM2 or its human equivalent, human double minute 2, HDM2) and therefore prevents ubiquitination and degradation of p53 (23; Figure 1, Table 1).…”

“…Among the different biological mechanisms that might account for renal aging somatic cellular senescence (SCS) has been proposed as a key contributor (16,(22)(23)(24)(25). SCS describes a phenomenon in which cells are still viable and Telomere attrition or dysfunction can activate p53 and p21 CIP1/WAF1 via the ATM/ATR kinases.…”

“…This response involves activation of phosphatidylinositol 3 kinase-like kinases, such as ataxia telangiectasia mutated (ATM) or ataxia telangiectasia mutated and Rad3 related (ATR) ( Figure 1; Table 1). These kinases activate downstream factors that halt DNA replication and other cellular proliferative processes by p53 phosphorylation (23). Active p53 is able to initiate apoptosis or senescence via transcriptional upregulation of proapoptotic genes or cyclin-dependent kinase inhibitor p21 CIP1/WAF1 , which leads to hypophosphorylation of retinoblastoma protein (Rb; Figure 1).…”