Cellular Senescence in the Kidney

Marie-Helena Docherty, Eoin D O'Sullivan, Joseph V Bonventre, David A Ferenbach, Marie-Helena Docherty, Eoin D O'Sullivan, Joseph V Bonventre, David A Ferenbach

Abstract

Senescent cells have undergone permanent growth arrest, adopt an altered secretory phenotype, and accumulate in the kidney and other organs with ageing and injury. Senescence has diverse physiologic roles and experimental studies support its importance in nephrogenesis, successful tissue repair, and in opposing malignant transformation. However, recent murine studies have shown that depletion of chronically senescent cells extends healthy lifespan and delays age-associated disease-implicating senescence and the senescence-associated secretory phenotype as drivers of organ dysfunction. Great interest is therefore focused on the manipulation of senescence as a novel therapeutic target in kidney disease. In this review, we examine current knowledge and areas of ongoing uncertainty regarding senescence in the human kidney and experimental models. We summarize evidence supporting the role of senescence in normal kidney development and homeostasis but also senescence-induced maladaptive repair, renal fibrosis, and transplant failure. Recent studies using senescent cell manipulation and depletion as novel therapies to treat renal disease are discussed, and we explore unanswered questions for future research.

Keywords: acute renal failure; chronic kidney disease; fibrosis; kidney development; progression of renal failure.

Copyright © 2019 by the American Society of Nephrology.

Figures

Figure 1.
Figure 1.
Pathways to cellular senescence in eukaryotic cells. Multiple discrete cellular insults act via distinct signaling mechanisms to induce cell-cycle arrest in the kidney at either the G1/S (via inhibition of cdk2 and/or cdk4/6) or G2/M checkpoints (via Chk1/2 activation or cdc2/25c inhibition). Inactivation of oncogenes and spindle/epigenetic/nucleolar stress trigger activation of the cyclin-dependent kinase inhibitor p16ink4a. Telomere shortening, DNA damage, mitogen or oncogene activation, and hypoxia/reoxygenation also result in G1/S cell-cycle arrest, via a pathway dependent on p53 and p21cip1 activation. In contrast to this, developmental senescence appears to induce p21cip1 by pathways mediated by TGFβ/PI3K and independent of p53. ATM/ATR/ARF, Ataxia–Telangiectasia Mutated/Ataxia Telangiectasia and Rad3-related protein/p14 Alternate Reading Frame (human).
Figure 2.
Figure 2.
Renal disease increases renal expression of the cyclin-dependent kinase inhibitor p16ink4a. (A) Normal kidney biopsy specimen from a 42-year-old living related donor with p16ink4a staining in some tubular epithelial cell nuclei. (B) Membranous nephropathy from a 64-year-old man demonstrating cytoplasmic and nuclear p16ink4a in tubular epithelium and interstitial nuclei (arrows). (C) FSGS biopsy specimen from a 48-year-old man, showing increased p16ink4a staining in some tubules and interstitial cell nuclei (arrows). (D) Grade 5 IgA nephropathy, with p16ink4a staining demonstrating increased cytoplasmic and nuclear staining. (E) Implantation biopsy specimen from a 45-year-old donor with expected low levels of p16ink4a-positive staining. (F) Repeat biopsy specimen of the same kidney 7 years post-transplantation demonstrating intense nuclear and cytoplasmic staining (note that the anti-p16ink4a [F12] antibody from Santa Cruz Biotechnology used in all of these images is no longer available).
Figure 3.
Figure 3.
The potential tissue effects of pathologic growth arrest in maladaptive repair. This flow chart illustrates the putative steps required for repair after AKI. In the case of adaptive repair, acute senescence is induced but then cleared in a tightly controlled manner, with normal tissue structure being restored by proliferation of resident cells. In maladaptive repair, it is recognized that there is an accumulation of both tissue fibrosis and secondary senescent cells. Recent studies indicate that pharmacologic/genetic targeting of senescent cells may protect against progressive fibrosis in murine models of aging.,
Figure 4.
Figure 4.
Current and potential future interventions to target growth-arrested cells in the kidney in vivo. Multiple points in the generation of senescent cells are under investigation as potential windows to alter their accumulation and/or pathogenic effects. Interventions are being trialed to prevent senescent cell formation (e.g., weight loss, exercise), promote senescent cell apoptosis (e.g., FOXO4-DRI, ABT-263), inhibit SASP release (e.g., sirolimus, metformin), or utilize the metabolic activity of senescent cells to activate compounds (e.g., galacto-oligosaccharide–conjugated drugs). shRNA, short hairpin RNA.
Figure 5.
Figure 5.
Unanswered questions about the roles and significance of senescent cells in the kidney. Several key questions regarding the role of the senescent cells in the kidney require ongoing research, with the goal of (1) quantifying senescent cell load noninvasively, (2) understanding the need for senescent cells in renal repair after injury, (3) determining the factors preventing senescent cell clearance from the kidney, and (4) testing the efficacy of senescence-modifying interventions in man.

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