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Published in final edited form as: Hypertension. 2020 Aug 31;76(4):1069–1075. doi: 10.1161/HYPERTENSIONAHA.120.14594

Cellular Senescence: A New Player in Kidney Injury

Yongxin Li 1,2, Lilach O Lerman 1
PMCID: PMC7484413  NIHMSID: NIHMS1617644  PMID: 32862712

Abstract

Kidney diseases secondary to several etiologies affect millions of people worldwide and have become increasingly recognized as a global public-health problem. Recent evidence suggests that cellular senescence plays an important role in the pathogenesis of different forms of renal damage, including acute and chronic kidney disease, and renal transplantation. Renal senescence involves cell-cycle arrest and affects several cellular pathways, manifesting in down-regulation of klotho, elevated expression of cyclin-dependent kinase inhibitors, cellular telomere shortening, and oxidative stress. Furthermore, senescent cells might induce kidney injury by paracrine release of inflammatory factors. Yet, cellular senescence may be renoprotective during development and in some models of renal diseases, reflecting the yin/yang duality of cellular senescence. This review provides an overview of the role of this emerging player in renal injury, with emphasis on new findings of cellular senescence.

Keywords: Senescence, Kidney, Chronic Kidney Disease, Acute Kidney Injury

Introduction

The elderly population is increasing in numbers worldwide. This introduces a challenge for healthcare providers, as the elderly are more vulnerable to diseases, possibly secondary to damage and decreased function of various organ systems during aging. Alas, the kidney is among the most susceptible organs to aging [1].

Kidney aging may induce microvascular and nephron loss and interstitial fibrosis [2]. Their pathogenesis involves activation of injurious pathways, including release of cytokines and growth factors, apoptosis, increased abundance of reactive oxygen/nitrogen species (RONS), and advanced-glycation end-products (AGE). Additionally, genetic changes, diet, and comorbidities play important modulatory roles, aggravating nephron loss [2]. Furthermore, while in healthy aging these changes might be mild, the aged kidney becomes more susceptible to develop or fail to recover from acute kidney injury (AKI), thereby progressing and increasing the incidence of chronic kidney disease (CKD).

A fundamental process manifesting amplified (and premature) features of aging is cellular senescence, yet accumulating evidence supports the notion that it in fact represents cellular response to a wide range of stressful stimuli. Cellular senescence is characterized by cell-cycle arrest, development of a pro-inflammatory senescence-associated secretory phenotype (SASP), macromolecular damage, and metabolic disorders. Although common, no unique marker categorically identifies senescent cells. Indices of senescence include upregulation of cell-cycle inhibitors (including p16, p21 and p53), senescence-associated β-galactosidase (SA-β-gal) activity, lamin-B1, activin-A, γ-H2AX, and DcR2, as well as telomere shortening. SASP is a distinct secretome of senescent cells, characterized by release of cytokines, growth factors, chemokines, and proteins [3]. Senescent cells are not only be damaged, but also exert far-reaching effects on neighboring cells by releasing paracrine pro-inflammatory and pro-fibrotic factors, like TGF-β, plasminogen-activator inhibitor-1, interleukin-6, and connective tissue growth-factor [4,5]. Due to this humoral amplification, few senescent cells are capable of imposing a harmful impact on both adjacent and remote organs.

Kidney senescence is perceived as invariably harmful, yet recent research has identified its beneficial role during development and response to injury. These intriguing notions exemplify the dual role of cellular senescence in renal physiology and pathophysiology. This review summarized the role of cellular senescence in the pathogenesis of renal injury, with emphasis on recent findings.

Type of senescent cells involved in renal injury

Different types of cells along the nephron and within the interstitium regulate renal function and vitality, and their proclivity to develop cellular senescence depends on the specific insult and its duration. Senescent cells are found in both the cortex and medulla of injured kidney, including tubular, glomerular, stromal, and vascular cells. Tubular epithelial cells (TEC), the major component of the cortex, are often the main targets for renal insults, and play an important role in the occurrence and development of AKI [6]. Moreover, these cells may mediate maladaptive repair during progression of chronic injury through development of interstitial fibrosis.

In CKD, markers of senescence have been observed in endothelial cells, podocytes, mesangial and parietal epithelial cells. Senescent cells have been identified in diabetic nephropathy (DN), membranous nephropathy, glomerulonephritis, focal-segmental glomerular sclerosis, and minimal-change disease [3]. In hypertensive kidney disease, vascular and interstitial cells may be the primary senescent cell types [7]. Hence, the chronicity and site of injury inflicted might dictate the cells and mediators involved in cellular senescence in the kidney. This distinction may also have important implications for future development of targeted therapies.

Cellular Senescence in AKI

Defined by a rapid increase in serum creatinine and/or decrease in urine output, AKI has increased in incidence over the last decades, often consequent to nephrotoxic drugs, sepsis, hypertension, obstruction, and/or ischemia-reperfusion injury (IRI). Many mechanisms contribute to cellular damage in AKI, including hypoxia, cell skeleton breakdown, influx of inflammatory cells, fibrosis, and microvascular loss. AKI induces cell-cycle arrest in the G2/M phase, which magnifies fibrosis [8]. Increasing evidence suggests that cellular senescence has an intimate relationship with patho-mechanisms of AKI, as they share down-regulation of klotho, upregulation of cyclin-dependent kinase inhibitors (CDKi), telomere-shortening, and oxidative stress [9–11]. Down-regulation of klotho in AKI may promote senescence and maladaptive recovery following AKI12. In addition, Notch signaling is activated in IRI AKI models, in turn activating p21 and p16INK4a and enhancing interstitial fibrosis [13,14].

Furthermore, AKI may predispose kidneys to CKD via accumulation of senescent cells during aging and post-injury, and in turn CKD patients are more prone to AKI upon injury. Hence, AKI-induced senescence may constitute a pivotal nexus in AKI-CKD progression.

Down-regulation of

Klotho is an anti-aging gene mainly expressed in both distal and proximal convoluted tubules, which contributes to renal homeostasis. Klotho can suppress Wnt signaling, which prolongs the cell-cycle by arresting it at G2/M, so that klotho loss may contribute to kidney injury.15 Indeed, down-regulated klotho expression was found in both IRI mouse models and AKI patients. In cultured cells, exogenous klotho decreases senescence, whereas knockdown of endogenous klotho elevates it [16]. Additionally, klotho gene overexpression extends the lifespan of mice by inhibiting insulin and IGF1 signaling [17], and elevates p53 and antioxidant enzyme genes10. Similarly, restoration of klotho and its antioxidant and anti-inflammatory effects during post-AKI repair retards senescence. Possibly, biological pathways associated with this ‘anti-aging gene’ might be related to its inverse relationship with cellular senescence.

Elevated expression of CDKi

The CDKi p21Waf1/Cip1 and p16ink4a-rb are key regulators of cell senescence. While p16INK4a expression is low-to-undetectable in youth, it is elevated in adults and the elderly, as well as in diseased kidneys and deteriorating renal allografts [18–20]. Conversely, blunted p16INK4a and p19 expression reduces cellular senescence and extends cell life. During IRI, expression of the CDKi p21Waf1/Cip1, p53, and p16INK4a is up-regulated, promoting cell-cycle arrest [21]. Likewise, in AKI, loss of p16INK4a promotes proliferation of regenerated cells and improves prognosis [22]. P21Waf1/Cip1 protein is also over-expressed in senescent cells [23].

TEC may manifest abnormal cell-cycle after AKI. In severe or repeated injury, the cell-cycle of TEC stagnates in G2/M phase, leading to activation of c-jun NH2 terminal-kinase and pro-fibrosis factors, including TGF (transforming growth factor)-β1 and connective tissue growth-factor [24]. TGF-β1 further promotes cell-cycle stagnation in G2/M phase, forming a vicious circle [25]. Recently, Wnt9a-TGF-β was implicated in senescence by exacerbating tubular senescence in IRI mice [26]. Therefore, AKI halts TEC proliferation by promoting cell-cycle arrest, which interferes with kidney regeneration and healing.

Telomere attrition

Telomeres located at the end of each chromosome are noncoding nucleotide TTAGGG sequences. Senescence may result from multiple cell divisions and telomere shortening (replicative senescence) in response to insults, such as oxidative or genotoxic injury. While human kidneys show telomere attrition at a normal rate of 0.25%/year, excessive telomere shortening in kidney disease may underlie cellular senescence.

Telomere shortening develops by 30 days after AKI in mice [9]. In telomerase reverse-transcriptase or -RNA knockout mice, recovery from AKI is delayed, with increasing TEC senescence and impairment of mTOR-mediated autophagy [27]. IRI injury eventuates in critical shortening of key telomeres due to cycles of injury and repair, leading to senescence and apoptosis in AKI and limiting renal ability to regenerate [9]. Potentially, telomere protection and restoration might represent important therapeutic targets to preserve cellular vitality.

Oxidative stress

AKI is associated with increased oxidative damage caused by an imbalance between reactive oxygen and nitrogen species (RONS) and antioxidant defense mechanisms, an important determinant of cell senescence. RONS can induce cellular senescence by regulating p16INK4a/prb and p53/p21 pathways, production of IL-1α and MMPs, and inhibition of FOXO (Forkhead box) proteins activity [28]. While the RONS/p53/p21 signaling pathway plays a vital role in senescence [29], senescent cells, in turn, produce RONS [30], perpetuating a vicious cycle of cellular damage. Oxidative stress can damage DNA, lipids and proteins, important steps of stress-induced cell senescence [29]. In addition, accumulation of RONS results in lipid peroxidation, which leads to elevated AGE and advanced lipoxidation end-products (ALEs), both of which regulate cellular senescence [31]. One of the shared links between oxidative stress and cellular senescence might be inflammation, which drives and results from both processes and contributes to AKI.

ROS/JNK/p38 signaling also mediates autophagy-delaying MSC (mesenchymal stem/stromal cells) senescence [32]. Urea-induced RONS generation also accelerates human EPC (endothelial progenitor cells) senescence and leads to SASP. These observations highlight the critical role of renal oxidative stress in senescence during AKI, and the capability of senescence to not only induce renal damage, but also interfere with endogenous repair mechanisms.

CKD

CKD is increasingly recognized as a global public-health problem. Causes of CKD associated with senescence include ischemic injury, hypertension, diabetes, polycystic kidney disease (PKD), and glomerulonephritis, and its impact on the kidney varies with disease etiology.

Ischemic Injury

Ischemia is common to many forms of renal disease. Renal microvascular diseases, including advanced diabetes and hypertension, are associated with reduced perfusion, but global kidney ischemia is best exemplified in renal artery stenosis, an escalating cause of CKD in the elderly.

While activation of cellular senescence in acute hypoxia and ischemia is well-established, it is an emerging driver of maladaptive changes in chronic tissue ischemia as well. For example, in a swine model of renovascular disease (RVD) we found development of cellular senescence in the post-stenotic kidney. Cellular senescence was detected by staining for SA-ß-gal and heterochromatin foci, expression of phosphorylated-H2AX and p16/21/53, and evidence of SASP markers (PAI-1, MCP-1, TGFβ, and TNFα) [33](Figure 1A). Interestingly, improved mitochondrial function did not fully abolish cellular senescence, implicating additional factors in its pathogenesis. Furthermore, we found elevated levels of urinary exosomes positive for senescence markers (P16 and MCP-1) in patients with RVD [34], emphasizing the clinical relevance of cellular senescence in this disease.

Figure 1.

Figure 1.

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A.Senescence in normal and stenotic pig kidney detected by senescence-associated β-galactosidase staining (green), particularly in tubular cells. B.Renal Senescence can be induced by various insults, and potentially attenuated by targeted senotherapy. Release of SASP by senescent cells is involved in induction of secondary senescence and tissue fibrosis.

Hypertensive Injury

Hypertension accounts for nearly 30% of patients with end-stage renal disease. Hypertensive kidney injury is characterized by activation of oxidative stress, the renin-angiotensin-aldosterone system (RAAS) [35], and inflammation, which are closely linked to cellular senescence. We have also shown that circulating klotho levels were reduced in patients with essential and renovascular hypertension [36]. Plausibly, this might reflect kidney cellular senescence in hypertensive patients.

Besides a fall in klotho levels, we have identified mitochondrial damage during development of hypertension [33]. Interestingly, the numbers of p16+/SLC22A12+ exosomes were elevated in the urine of hypertensive patients, and may indicate increased proximal TEC senescence [34]. Furthermore, in essential hypertensive patients, levels of p16+/prominin-2+ exosomes were also elevated, representing release of EVs also from senescent distal TEC as well. Therefore, urinary EVs bearing parent cell markers may pinpoint nephron segments and cells vulnerable to specific insults and potentially also amenable to cell-specific intervention. Additional studies are needed to apply this notion to other forms of CKD.

Diabetic Nephropathy

DN is the leading cause of kidney failure, accounting for 44% of new cases [37]. Cellular senescence is involved in development of DN through a number of mechanisms.

Sustained hyperglycemia leads to oxidative stress, which damages DNA histones and affects expression of DNA repair enzymes [38]. DNA damage induces cellular senescence through ATM/ATR-p21axis [39], and evokes DNA damage-response, leading to activation of phosphatidylinositol-3 kinase-like kinases, and in turn P53 and its downstream p21CIP1/WAF1. p21CIP1/WAF1 inhibits retinoblastoma protein, leading to cell-cycle stagnation [39]. Mitochondrial damage also contributes to senescence-associated tissue injury in DN. One of the molecular mechanisms proposed involves optineurin, a crucial determinant of mitophagy, which participates in high-glucose-induced senescence in TEC [40].

Klotho also participates in cellular senescence in DN. At the earliest stage of DN, klotho begins to decline, leading to senescence of renal cells through the insulin/IGF-1, Wnt signaling, and others [41]. Moreover, klotho may have a reciprocal relationship with activin-A activity [42].

An accelerator of senescence, inflammation is a common pathological and multifactorial feature of CKD. Inflammatory factors directly induce renal damage, like the Nod-like receptor-3 inflammasome that stimulates maturation and secretion of IL-1ß and IL-18 by activating caspase-1 [43]. Consequently, senescence accelerates as autophagy is inhibited by proinflammatory cytokines [44]. NF-kB activated by high glucose recruits p300 and activates iNOS, increasing oxidative stress and inflammation [26]. Moreover, inflammation augments DNA damage, mitophagy, and other mechanisms involved in DN-induced cellular senescence, forming a complex cascade of renal injury. Circulating activin-A, an inflammatory mediator implicated in profibrotic kidney injury and senescence-induced adipose tissue dysfunction, is also elevated in patients with diabetes [3], consistent with its inverse relationship with klotho. Overall, release of inflammatory cytokines secondary to SASP is fundamental for the pathogenesis of DN.

A number of non-coding RNAs, including miRNAs (micro-RNA) and lncRNAs (long noncoding RNAs), participate in the pathogenesis of cellular senescence, such as miR-378i, mir-21, mir-34a, mir-200 families and lncRNA GSA5 [45–47]. miR-378i expression, positively correlated with urinary SASP cytokines and renal function, is upregulated in TECs by high glucose and can regulate senescence by targeting Skp2 in DN [46]. Contrarily, lncRNA GSA5 suppresses DN development by inhibiting mesangial cells proliferation and causing G0/1 phase arrest [47]. Additional studies are needed to evaluate non-coding RNAs as therapeutic targets in DN and other forms of CKD.

PKD

Interestingly, in PKD senescence might paradoxically blunt disease progression. Levels of p21 are decreased in kidneys from humans and non-transgenic rats with autosomal-dominant PKD (ADPKD), and inversely correlate with TEC proliferation [48]. Congruently, roscovitine, which blunts the disease, decreases TEC proliferation and increases p21 and senescence in murine ADPKD [49]. Expression of p57KIP2, another CDKi, is downregulated in renal cell lines from PKD transgenic rats, which involves TEC proliferation in ADPKD [49]. Therefore, senescence seems to inhibit cystic progression in PKD, underscoring the relevance of context and etiology in evaluating its contribution to renal pathophysiology.

Glomerulonephritis

Immunoglobulin-A nephropathy (IgAN), a common cause of adult CKD, might eventuate in loss of renal function. Senescence-related markers (SA-ß-gal, p21, p16) are increased in IgAN patients, correlating with the degree of renal interstitial damage, linking cell senescence to progression of IgAN [50]. Expression of p53 and iNOS in glomerular endothelium, epithelium, and tubules in IgAN patients is upregulated during progression of injury [51]. Similarly, p16 expression is also upregulated in glomerular cell nuclei in glomerular diseases [19]. Furthermore, SA-β-Gal activity increases in kidneys from lupus mice, correlating with glomerular lesion markers [52]. Therefore, senescence contributes to glomerulonephritis, and correlates with the severity of disease. Conceivably, anti-senescence therapy seems to be a promising approach.

Kidney transplantation

Development of cellular senescence might lead to chronic allograft nephropathy and graft loss. During kidney transplantation, IRI induces oxidative stress, senescence, and organ dysfunction [53]. Notably, kidney transplants with senescence phenotype from older donors are more susceptible to IRI, transplant dysfunction, and decreased survival compared with younger donors [54] underscoring the link between senescence and aging.

Several senescence-associated mechanisms have been observed in rats with chronic renal transplant rejection, including telomere shortening, p16/p21 upregulation, and enhanced SA-β-gal expression [55]. In a INK4a(−/−) kidney transplant mice, P16INK4a-dependent senescence is averted, resulting in improved TEC proliferation, lower interstitial fibrosis and tubular atrophy, and better survival rate after IRI [56]. Similarly, p16INK4a expression is increased in kidney transplantation and disease in human subjects [18].

Taken together, these results support the notion that senescence might be a rational therapeutic-target to arrest progression of chronic allograft dysfunction. Possibly, senolytic drugs might be considered for living donors pre-donation, for harvested kidneys in vitro, and/or for kidney transplant recipients.

Cellular senescence as a reno-protective process

While most evidence supports the adverse role of senescence in kidney repair after injury, in some context it might conversely be beneficial as described in PKD. Cells enter a senescent state to prevent proliferation of damaged cells, a risk factor for cancer and other diseases. In turn, senescent cells secrete pro-inflammatory, chemotactic SASP factors, which protect neighboring cells from the same insult and recruit immune cells to clear senescent cells. Cellular senescence participates in tissue-remodeling, like wound repair [57] and embryogenesis [58,59], in which senescent cells produced have a short half-life. In mice lacking key aging regulators, senescent hepatic stellate cells show decreased extracellular matrix secretion, increased degrading enzyme secretion, and enhanced immune surveillance [60]. Moreover, senescent fibroblasts and endothelial cells respond early to skin trauma by secreting platelet-derived growth-factor-AA to induce myofibroblast differentiation, accelerating wound-healing [57].

In the kidney, INK4a−/− mice with unilateral ureteral obstruction show increased cell proliferation, decreased senescence, and increased fibrosis [61], suggesting that INK4a may control kidney cell proliferation and stromal production in normal young mice. Contrarily, INK4a−/− IRI mice show lower serum creatinine levels, increased cell proliferation, decreased TEC apoptosis, and higher capillary density, suggesting that loss of p16INK4a and p19ARF improves epithelial and microvascular repair, possibly by enhancing mobilization of myeloid cells into the kidney [22]. Furthermore, CDK4/6 inhibition not only induces G0/G1 cycle arrest in proximal TEC after injury, but also ameliorates kidney injury and decreases epithelial proliferation and inflammation in murine IRI [11]. Therefore, cellular senescence might play a reno-protective role during some renal injury processes.

Given widespread apoptosis in early kidney injury, development of transient senescence might speculatively increase cellular survival by upregulation of BCL-2 family proteins, thereby bestowing resistance to apoptosis. Conversely, persistent senescence is maladaptive, because of incessant release of inflammatory SASP. Hence, cells that chronically accumulate damage ultimately reach a threshold of cellular stress that prompts permanent withdrawal from the cell cycle [62]. Clearly, the role of senescence is process- and timing-dependent. Thus, reversing senescence may not be invariably beneficial, and identifying specific cellular targets and injury phases suitable for intervention may help optimize anti-senescence approaches.

Therapy

Various approaches and novel senolytic agents have been applied to reverse the adverse impact of cell senescence (Supplementary Table 1). A screening discovery paradigm identified senolytic agents, including natural products, synthetic small molecules, and peptides that exhibit cell-type specificity [63]. In particular, the senolytic activity shown by some natural products and flavonoids introduces the prospect of interfering with this process with few adverse effects. The main strategies to blunt cellular senescence (Figure 1B) include prevention/suppression of senescence (senomorphics), senolytic drugs (selective senescent-cell apoptosis), stimulation of immune system-mediated senescent cell clearance [64], and inhibition of downstream SASP using anti-inflammatory platforms. Overall, drugs designed to eliminate senescence often restore tissue homeostasis, improving kidney function and extending longevity in mice.

For example, we have found that renal senescence induced by murine obesity and dyslipidemia impairs kidney function, and alleviated by senolytic treatment with a natural supplement (quercetin) [65]. Furthermore, in patients with DN senolytics (dasatinib+quercetin) decrease senescent-cell burden [66]. Contrarily, non-targeted approaches, like a mitochondria-targeted peptide, only partly attenuated senescence, yet improved renal function, fibrosis, and oxidative stress [33]. Therefore, interventions specifically targeted to senescent cells may be essential to blunt this pathway, although clearly senescence does not account for all aspects of renal dysfunction. Future insights and developments along this pathway are critically needed.

Summary

Animal and clinical studies have implicated cellular senescence in the pathogenesis of AKI, CKD, and allograft failure. Accumulation of senescent cells is common in renal injury, possibly owing to down-regulation of klotho, upregulation of CDKi, telomere shortening, oxidative stress, and other mechanisms. Senescence targeting might be useful to ameliorate kidney injury in animal models and shows promise in human subjects. However, distinguishing deleterious from protective senescence is critical, and requires further research in animal models and clinical trials. Hopefully, future developments will allow leveraging emerging tools to manipulate this fundamental process.

Supplementary Material

Supplemental Table

Acknowledgement

Partly supported by NIH grant numbers DK120292, DK122734, AG062104, and DK102325.

Ethics

Dr. Lerman receives grant funding from Novo Nordisk and advises Weijian Technologies and AstraZeneca.

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