Abstract: Cellular or replicative senescence is classically seen as the key element of aging. In renal disease and after kidney transplantation, there is increasing evidence that replicative senescence pathways (p53 and p16) play a central role in disease progression and graft outcome, independent of chronological age. In this review, we summarize the current concepts in the molecular mechanisms of cellular senescence, and correlate these theories with the available literature on aging of native kidneys, kidney diseases, and outcome of renal allografts. Recent data illustrate the complex biology of senescence in vivo, and disprove the concept that senescence is an intrinsic injury process with immanent deleterious consequences. Senescence acts as a homeostatic mechanism that can even limit renal fibrosis, at least in animal studies. In a human setting, it remains to be investigated whether cellular senescence plays an active or a bystander role in fibrogenesis and atrophy of renal tissue.
From the clinical studies and phenotypic data that are available, we know that older kidneys differ from younger ones in terms of function and morphology, that older kidneys have a distinct susceptibility to disease processes, and that the response to these disease processes is different in older kidneys compared to younger ones (Epstein, 1996; Zhou et al., 2008). Furthermore, with the increasing use of older donor kidneys for kidney transplantation, it is becoming clear that old donor age highly impacts on kidney transplantation outcome (Naesens et al., 2009b; Tullius et al., 2010). A better insight in the mechanisms underlying the impact of kidney age on renal disease progression and of donor age on post-transplant renal graft evolution could pave the way towards more targeted therapy.
Aging is a programmed biological process that is associated with small transcriptional differences in many genes, rather than with large expression changes in a small number of genes, as was shown by transcriptomic analysis (Weindruch et al., 2001; Rodwell et al., 2004; McCarroll et al., 2004; Melk et al., 2005a). The altered molecules with aging involve many different pathways, including cell integrity, cellular proliferation, cell transport, and energy metabolism. Many of these molecules and processes are not unique to aging, and are likely general pathways involved in tissue damage. The aging phenotype is the consequence of cellular or replicative senescence (irreversible growth arrest), increased susceptibility to apoptosis with older age, impaired regeneration and repair, decreased functional capacity of stem cells and progenitor cells, changes in the expression of growth factors with increasing age, mitochondrial changes, dysregulation of autoregulatory pathways, and immune system alterations and different immunogenicity of older tissue.
Cellular or replicative senescence is classically seen as the key element of aging. This phenomenon corresponds to permanent and irreversible growth arrest that was detected in seminal in vitro studies by Hayflick and Moorhead (1961). In this review, we summarize the current concepts in the molecular mechanisms of cellular senescence, and correlate these theories with the literature on aging of native kidneys and outcome after renal transplantation.
Cellular Senescence Signals
The senescent phenotype of cells, i.e., growth arrest, is induced by multiple stimuli, and cellular senescence is a specific response of mitotically active cells to various stressors. Replicative senescence, also called the Hayflick phenomenon, has been associated with telomere shortening and telomere dysfunction, non-telomere DNA damage (e.g., due to X-rays, oxidative stress, and UV irradiation), mitogenic signals including those produced by oncogenes (which also cause DNA damage), and non-genotoxic stress like chromatin perturbation (epigenetic changes) and other stress factors (Campisi and d’Adda di Fagagna, 2007; Finkel et al., 2007).
These stimuli induce cell senescence through two main pathways: an ARF-p53-p21 signaling pathway that is partially telomere dependent, and a p16-pRb pathway that is independent of telomere dysfunction. These pathways are dissociated with one another and can individually induce senescence, although there is also overlap and interaction (Campisi and d’Adda di Fagagna, 2007; Collado and Serrano, 2010). Notwithstanding the fact that the original observations by Hayflick and Moorhead were made in 1961 in cultured cells, only during the past decade or so has replicative senescence been demonstrated to occur and to be of importance in vivo.
Together these mechanisms limit excessive or aberrant cellular proliferation, and so the state of senescence protects against the development of cancer (Figure 1) (Finkel et al., 2007). Cell senescence is however not only important in tumor suppression, senescent cells have also been identified at sites of degenerative age-related pathologies, and it is conceived that cellular senescence actively drives aging and age-related pathology (Figure 1) (Campisi, 2010). From a teleological point of view, in accordance to the current evolution theory, aging-related pathology and tissue disruption could then be seen as the consequence of the declining force of natural selection with increasing age, as natural selection against processes that promote late life disabilities (after the reproductive age) is weak.
Recently, however, it is becoming clear that senescence is not only a tumor suppressive failsafe response to stress factors with deleterious side effects on tissue integrity. Cellular senescence also comprises protective effects and is associated with tissue repair (Figure 1). Studies have shown that senescent cells can function to communicate cellular damage or dysfunction to the surrounding tissue, and resolve tissue damage through inflammatory cytokine secretion by the senescent cells (Jun and Lau, 2010a; Rodier et al., 2009). From an evolutionary biology viewpoint, it could be postulated that cell senescence evolved to promote tissue repair in young organisms, next to tumor suppression (Campisi, 2010). As the role of cellular senescence in wound healing and tissue repair is only beginning to be appreciated, many questions still remain unanswered and more work on the importance of senescence pathways for tissue repair is indispensable.
Telomere Shortening and the p53 Pathway
Telomeres are DNA-protein complexes located at the end of chromosomes which prevent end-to-end fusion of chromosomes and thus sustain chromosomal stability. Telomeric DNA is synthesized by telomerase and consists of TTAGGG tandem repeats in humans. The shelterin proteins, which coat the telomeric DNA sequence, serve as molecular signal to prevent the cellular DNA repair machinery from mistaking telomeres for double-stranded DNA. As most somatic cells don’t express telomerase, the telomeres shorten with each cell division, and when the telomeres become critically short (reach the “Hayflick limit”), a classical DNA-damage response is triggered with participation of several protein kinases (e.g., ATM and CHK2), adaptor proteins (e.g., 53BP1 and MDC1), and chromatin modifiers (e.g., γH2AX).
Telomere shortening leads to activation of the p53 pathway (through p53 phosphorylation), and herewith associated p21 (also termed CDKN1a, p21Cip1, Waf1, or SDI1) expression, although this activation is not exclusive for telomere shortening and is also seen with other stimuli that generate DNA damage responses (DDRs). This leads to cell cycle arrest and thus replicative senescence. ARF (alternate reading frame; called p19 in mice and p14 in humans), which is encoded by CDKN2A, also engages the p53 pathway. For a comprehensive overview of the current insight in the role of telomere biology in replicative senescence, we refer to reviews by Campisi and d’Adda di Fagagna (2007) and Deng et al. (2008). Finally, the p53 pathway can also be engaged and induce senescence by DNA-damage responses (DDRs) other than telomere shortening (Jackson and Bartek, 2009), while the SIRT1 (sirtuin 1) can negatively regulate p53 localization to the nucleus and its function as a transcription factor. It is beyond the scope of this review to highlight the determinants of SIRT1 expression and its action mechanisms; we refer to a recent paper by Brooks and Gu (2009).
Telomere shortening is an inevitable physiological consequence of somatic cell division and therefore of older age, but telomere length is also influenced by environmental factors and genetic alterations like telomerase mutations (Calado and Young, 2009). Telomerase (with its catalytic protein component TERT and RNA component or template TERC) is an enzyme that prevents telomere shortening by adding telomeric DNA repeats directly to chromosome ends, but most normal somatic cells do not express telomerase and telomere length therefore declines with each cell cycle (Campisi and d’Adda di Fagagna, 2007). Interestingly, especially with respect to the field of transplantation, telomere shortening also occurs in graft-derived leukocytes after bone marrow transplantation significantly more rapidly than would be expected (Wynn et al., 1998). This accelerated telomere shortening of blood cells after bone-marrow transplantation is intriguing, and likely relates to the increased replicative demand on recently engrafted stem cells (Akiyama et al., 2000).
Telomere shortening and p53 in native kidneys
In contrast to, e.g., blood cells, the association between age and telomere shortening in renal tissue was studied only scarcely. In adult human kidneys, telomerase activity is low and the cells contain short telomeres. It has been demonstrated that renal telomere DNA is lost with increasing age and the rate of loss in cortex is greater than in the medulla (Melk et al., 2000). Furthermore, the length of telomere DNA in renal cortex declines at a rate intermediate between highly proliferative cells such as lymphocytes and less proliferative tissues such as brain or muscle, in which telomere shortening is not detected. It is however interesting to note that Melk et al. (2004) did not see a correlation between renal age and p21 or p53 expression, which illustrates that the expression of these markers is not directly linked to telomere length and that factors other than chronological age contribute to the activation of the p53 pathway and subsequent renal senescence (Table 1).
Indeed, next to chronological age, accelerated telomere shortening was also described in kidneys secondary to ischemia in rats (Joosten et al., 2003; Kelly et al., 2003), and p21 is increased after renal ischemia in mice (Hochegger et al., 2007; Megyesi et al., 1996). The ARF-p53 pathway was also shown to regulate the cell cycle after ischemic injury in rats (Tanaka et al., 2005), and p21 expression was associated with the duration of ischemia time in an ex vivo model of renal hemoperfusion in pigs (Chkhotua et al., 2006). In cynomolgus monkeys, however, ischemia and reperfusion did not significantly affect telomere length (Chkhotua et al., 2005), although this small study definitely needs validation.
In vitro, hyperglycemia induces accelerated telomere shortening in tubular epithelial cells (Verzola et al., 2008), which is in concordance with other studies that demonstrate an association between diabetes mellitus and decline in telomere length (Avogaro et al., 2010). Also oxidative stress by hydrogen peroxide (H2O2) was associated with regulation of p21 and p53 expression in an in vitro analysis on proximal tubular epithelial cells (Yoshida et al., 2008), and this is likely an explanation for the effects of cyclosporine on p53 activation and p21 expression in renal tubular epithelial cells (Yang et al., 2002; Jennings et al., 2007).
Finally, glomerular diseases like IgA nephropathy, lupus nephritis, and focal glomerulosclerosis are associated with increased p53 expression compared to kidneys without lesions, in animals (Turner et al., 2007) and in humans (Takemura et al., 1996; Qiu et al., 2004).
In light of the impact of hypertension on p16 expression (see below), it is interesting to note that the p53-p21 pathway appears to be unaltered in response to hypertension, at least in vitro and in the absence of hyperglycemia (Efrati et al., 2007). In cultures exposed to high glucose levels, however, hypertension induced p53 expression and inhibition of p53 decreased hypertension-associated apoptosis (Efrati et al., 2009). Whether this is relevant in vivo has not been tested to date.
What are the consequences of telomere shortening of renal cells (Table 2)? Melk et al. (2000) have described telomere shortening in older kidney tissue, but there was no significant association between telomere length and renal function. Until recently, the presumed association between telomere shortening and decreased renal repair/regeneration after injury was largely unproven, and in humans, this is still the case. A recent animal study however has demonstrated that susceptibility to acute cell death and reduced long-term regeneration is increased in murine kidneys with critically short telomeres, as induced by knocking-out TERC, the RNA component of the telomerase complex (Westhoff et al., 2010).
In addition, the p53 pathway has recently been shown to be of major importance in renal fibrogenesis after acute injury, in both toxic and obstructive/ischemic models of acute renal injury (Yang et al., 2010). Also other studies have related p53 pathway activation to renal fibrosis, e.g., secondary to indoxyl sulphate (Shimizu et al., 2010) and ischemia-reperfusion injury (Kailong et al., 2007) and with obstructive nephropathy (Choi et al., 2001). Furthermore, silencing of p53 by siRNA attenuates ischemic and cisplatin-induced acute kidney injury, in terms of both histological lesions and renal function (Molitoris et al., 2009). Activation of p53 can lead to either apoptosis or senescence (permanent or transient), but how cells “decide” to undergo a transient growth arrest, permanent replicative senescence, or apoptosis in response to damage or stress signals is currently not clear, and both apoptosis and senescence can occur simultaneously (Deng et al., 2008; Campisi and d’Adda di Fagagna, 2007).
Interestingly, in one study, p21 appears to be protective against the effects of renal ischemia, as p21 knockout mice had increased susceptibility to ischemia-induced acute renal failure, likely due to the inhibitory effect of p21 on cell cycling (Megyesi et al., 2001), while other studies using inhibitors showed opposite effects (Hochegger et al., 2007; Kelly et al., 2003). To date, it is not known whether the observed upregulation of p21 is a protective or harmful mechanism of renal tubular cells, and further research is necessary to shed light on the exact role of the p53-p21 pathway on fibrogenesis vs. tissue repair. For a comprehensive review on the protective effects of cell cycle inhibition and hypothesis on the role of p21 on tissue repair, we refer to recent reviews (Price et al., 2004; Price et al., 2009; Campisi, 2010).
Telomere shortening and p53 in kidney transplants
After solid organ transplantation, there are arguments to state that transplantation is associated with accelerated shortening of telomere length in the transplanted cells (Table 1). There is some evidence that there is an increased cell turnover in kidney allografts at the time of transplantation (Oberbauer et al., 1999). In the initial phase after transplantation, proliferating cell nuclear antigen (PCNA) analysis showed that there is a phase of increased epithelial cell regeneration directly after transplantation, which correlates with cold ischemia time (Vinuesa et al., 2008). Under normal circumstances, renal tubular cells are quiescent and do not readily divide in response to growth factors. After an ischemic insult, however, surviving renal tubular cells re-enter the cell cycle and replicate, and replace irreversibly injured cells (Price et al., 2009). This increased epithelial cell turnover could well be associated with telomere attrition, although this remains to be demonstrated and a small and poorly controlled study in primates suggests that this is however not the case (Schelzig et al., 2003). Further research is necessary to elucidate the effects of peritransplant ischemia and reperfusion on cell turn-over and telomere biology.
It has also been shown that lymphocytic telomere shortening can occur secondary to viral infections like CMV infection (van de Berg et al., 2010) but also bacterial infections (Ilmonen et al., 2008), which could also play a role after transplantation with patients being more susceptible to infectious problems, particularly CMV-associated disease. Whether other inflammatory processes (e.g., graft rejection) also lead to telomere shortening, eventually in the target organ like a kidney allograft, is not known but is worth additional research.
In humans, shorter telomere length in kidney biopsies obtained at implantation of a renal allograft was independently associated with lower graft function at 12 months after transplantation (Koppelstaetter et al., 2008). In this small study, there was however neither a correlation between p21 expression at implantation and graft function, nor was there a correlation between p21 expression and donor age. A similar absence of correlation between renal age and p21 or p53 expression was noted in a human study by Melk et al. (2004). Likewise, ARF was not associated with kidney age in this study. Interestingly, p53 expression correlated significantly with tubular atrophy and glomerulosclerosis, thus independent of renal age, and ARF expression correlated with tubular atrophy (Melk et al., 2004). How to interpret this finding is currently unclear, but one could hypothesize that the p53 pathway is not the main contributor to chronic histological damage in older kidneys, and that other pathways (like p16) are more important (see below). Further studies are necessary to elucidate the exact role of telomere shortening and the p53 senescence pathway in older kidneys and fibrosis progression (Table 2).
It is interesting to note that cyclosporine can induce decline in telomere length, p53 activation (through phosphorylation), and p21 expression in renal tubular epithelial cells, probably through production of reactive oxygen species (Yang et al., 2002; Jennings et al., 2007). After treatment with cyclosporine, cells were arrested in the G0/G1 phase of the cell cycle, which could be independently observed by a cyclosporine dose-dependent decrease in DNA synthesis without alterations in viable cell number. In addition, there was no cyclosporine-mediated induction of apoptosis, suggesting that the severity of telomere-mediated cell cycle arrest was mild enough to induce senescence without programmed cell death (Jennings et al., 2007). Of note, not only the p53-p21 pathway of senescence was induced, but also the p16 expression was increased upon treatment with cyclosporine (see below). Whether this plays a role in progressive cyclosporine nephrotoxicity (Naesens et al., 2009a) is currently unclear.
Finally, there is a suggestion that the number of acute rejection episodes correlates with decreased telomere length (Chkhotua et al., 2003a). However, the patient cohort in this study was too small to make firm conclusions, and selection bias could have affected the results. In a prior animal study, it was found that at 60 days after transplantation, syngeneic transplants had a similar reduction in telomere length as allogeneic transplants, and this telomere shortening was correlated with ischemia-reperfusion rather than with alloimmune responses (Joosten et al., 2003). In this latter study, subsequent p21 expression was however not sufficient to induce senescence-associated beta-galactosidase (SA-βgal, a biomarker for senescent and aging cells), which suggests that an additional event is required to induce cellular senescence, and this could well be a process driven by alloimmunity as it was only seen in the animal model leading to chronic rejection (Joosten et al., 2003).
Upregulation of the p16-pRB Pathway
Signals that produce DNA-damage responses can also engage the p16-pRB pathway, especially in epithelial cells (Campisi and d’Adda di Fagagna, 2007). p16 expression reflects primarily environmental stress, although dysfunctional telomeres can also induce p16 expression (Campisi and d’Adda di Fagagna, 2007). This telomere-independent senescence pathway is currently often referred to as “STASIS” (Stress and Aberrant Signaling-Induced Senescence).
p16 is encoded by CDKN2A, which also encodes ARF, an important tumor suppressor in the p53 pathway (Campisi and d’Adda di Fagagna, 2007). p16 keeps pRB in an active hypophosphorylated form, which inhibits cell proliferation and induces growth arrest through the effects of pRB on E2F (Campisi and d’Adda di Fagagna, 2007). The p53 and p16-pRB pathways interact with each other, and there is reciprocal regulation between the p53 and p16-pRB pathways. However, both pathways can independently halt cell-cycle progression. In addition, p16 is now used to identify senescent cells, as it is expressed by most (but not all) senescent cells (Krishnamurthy et al., 2004).
p16-pRB in native kidneys
In human kidneys, cortical p16 mRNA and protein expression correlate significantly with kidney age, both in rodents (Krishnamurthy et al., 2004) and in humans (Table 1) (Chkhotua et al., 2003b; Melk et al., 2004; McGlynn et al., 2009).
Next to chronological age, glomerular and tubulo-interstitial expression of p16 appears to be increased in human kidneys with various glomerular diseases, beyond that predicted for normal aging (Melk et al., 2005b; Sis et al., 2007), and there is a significant correlation between p16 expression and interstitial fibrosis in biopsies of patients with glomerular disease (Sis et al., 2007).
Furthermore, p16 expression was also induced in diabetic nephropathy, both in animals (Wolf et al., 1999; Wolf, 2000) and in humans (Verzola et al., 2008), independent of chronologic age and correlating significantly with HbA1c levels.
Increased renal p16 expression was also seen in hypertensive animals and humans, while treatment of hypertension attenuated p16 expression and amelioration of the histopathologic changes associated with hypertension (Westhoff et al., 2008).
It has also been demonstrated that p16 expression relates to ischemia-reperfusion, at least in mice (Hochegger et al., 2007). In this study, p16 gene and protein expression was strongly dependent on the reperfusion time and could not differentiate between long and short periods of ischemia. A similar association between ischemia-reperfusion and p16 expression was observed in an ex vivo perfusion model of pig kidneys (Chkhotua et al., 2006). It remains unclear whether this is important in the human situation, as a study with implantation biopsies at the time of transplantation did not show a correlation between cold ischemia time and CKDN2A expression (see below) (McGlynn et al., 2009).
In vitro, cyclosporine induced renal tubular p16 expression, and this is potentially related to the nephrotoxicity of this drug (Jennings et al., 2007). The importance of this finding in vivo remains to be elucidated.
Furthermore, catch-up growth in low-birth weight animals correlated with increased p16 expression in native kidneys (and also p21 expression), and this was associated with increased expression of p66Shc and Ero1α, suggesting increased production of reactive oxygen species (Luyckx et al., 2009). The pathophysiology underlying this accelerated aging in animals with catch-up growth is however not clear.
Finally, age-associated p16 expression in the kidney is attenuated with caloric restriction in animals, and this decrease correlates with decreased SA-βgal expression (Krishnamurthy et al., 2004), which is the single most accepted and widely used marker to identify senescent cells (Collado and Serrano, 2010). The expression of the proliferation marker Ki-67 was significantly associated with p16 expression (Melk et al., 2004), although this last correlation was very weak and it has to be noted that Ki-67 is not very specific for aging.
Renal p16 expression correlated with glomerulosclerosis, interstitial ﬁbrosis, and tubular atrophy in “normal” (non-diseased) kidneys from older individuals (Table 2) (Melk et al., 2004). Although the association between p16 expression and renal fibrosis, atrophy, and glomerulosclerosis could suggest a causal relationship, this has been contested by recent studies. Indeed, Wolstein et al. (2010) demonstrated recently that p16 knockout mice (without cell senescence evidenced by senescence-associated β-galactosidase staining) in normal conditions or after postrenal obstruction displayed 10-fold increased tubular and interstitial cell proliferation, decreased collecting duct apoptosis, and greater collagen and fibronectin deposition compared with wild-type mice. This suggests that increased p16 expression following injury acts to limit excess cell proliferation and inflammation, thus resulting in decreased kidney fibrosis. This is the contrary of the previous theory that accelerated senescence is a cause of chronic histological damage (Halloran et al., 1999).
These findings illustrate the complex biology of senescence in vivo, and disproves the concept that senescence is an intrinsic injury process with immanent deleterious consequences (Halloran et al., 1999). Senescence may therefore act as a homeostatic mechanism that may even limit tissue fibrosis, as was recently demonstrated in a mouse model of reversible liver fibrosis (Krizhanovsky et al., 2008) and in cutaneous wounds (Jun and Lau, 2010b). The complex relationship between the deleterious effects of cell senescence on tissue integrity and the effects of senescence on tissue repair are recently reviewed by Campisi (2010), but further research is necessary to clarify the impact of these findings in a human setting (Figure 1, Table 2).
p16-pRB in kidney transplants
Senescence associated with activation of the p16 pathway appears to be important after renal transplantation. In a study in older-aged mice, with increased p16 expression (but not telomere shortening, as telomere shortening is not occurring in mice), transplantation of older kidneys was associated with more pronounced post-transplant histological alterations like tubular basement membrane wrinkling, but also significant and rapid increase in p16 expression after transplantation, while p16 expression increase was slower and less pronounced in younger animals (Melk et al., 2009). This reflects both a higher basal expression of p16 and a greater expression induction in older animals. Importantly, the older animals had significantly lower expression of Ki-67 after transplantation, which is a marker of proliferation and thus regenerative capacity of the epithelial cells (Melk et al., 2009). Whether these findings in mice (that lack telomere shortening) are also valid in humans remains to be studied.
In human kidney transplantation, CDKN2A expression in implantation biopsies was the dominant factor associating with donor age and post-transplantation graft function (Koppelstaetter et al., 2008). CDKN2A expression also correlated with both donor age and graft function, while telomere length did not (Koppelstaetter et al., 2008). More so, CDKN2A expression at implantation was a better predictor for graft function at 6 and 12 months after transplantation than chronological age (McGlynn et al., 2009).
In post-transplant biopsies of renal allografts showing interstitial fibrosis and tubular atrophy, the predicted age from p16 expression in cortical tubules was significantly higher than the chronological age of these grafts, which could illustrate upregulation of this senescence pathway, or “accelerated senescence” (Chkhotua et al., 2003b). This association between interstitial fibrosis/tubular atrophy of renal allografts and increased p16 expression was also described by others (Ferlicot et al., 2003), which concurred with decreased graft function (Melk et al., 2005b). p16 expression in kidneys with stable graft function was within the range predicted for kidney age, while p16 expression was significantly higher than expected in kidneys with deteriorating function, interstitial fibrosis, and tubular atrophy (Melk et al., 2005b).
The reason for increased p16 expression after kidney transplantation is currently not clear (Table 1). The finding that p16 expression remained similar to baseline after isografting and the significant increase in p16 expression after allogeneic transplantation suggests that allo-reactive processes and rejection affect p16 biology in allografts (Melk et al., 2009). Similarly, it was shown in rats that allogeneic transplantation was associated with upregulation of p16 expression (Joosten et al., 2003). Interestingly, however, the situation where SA-βgal expression was increased in association with chronic rejection could suggest that SA-βgal plays a role in or is associated with the fibrosing process, and p16 expression in itself is not sufficient for fibrogenesis (Joosten et al., 2003).
However, non-immune phenomena likely play a role in the increase in p16 expression post-transplantation, like the longer-term use of cyclosporine (see above) (Jennings et al., 2007), which is known to induce chronic histological damage (Naesens et al., 2009a).
Finally, it was found that renal p16 expression correlates with reperfusion time, but not with the longer ischemia time (Hochegger et al., 2007). Whether this finding is also relevant for human clinical transplantation is currently not sorted out. Interestingly, in one human study, there was no correlation between cold ischemia time and p16 expression (McGlynn et al., 2009).
In contrast to what is possible in animal studies, in humans it is not possible to conclude causality between p16 expression and progressive renal allograft damage from the few association studies that have been published to date (Table 2). Furthermore, it remains very difficult to assess the relative contribution of aging, alloimmune responses, ischemia-reperfusion injury, and other post-transplant phenomena to chronic allograft damage in a human setting. Melk et al. (2005b) have made some major steps forward in this field, and demonstrated increased p16 expression in dysfunctional kidneys. This study supports the idea that injury processes associate with senescence phenomena, but whether this is a causal relationship or not, and in what direction the causality would be, remains unknown. Accelerated senescence could induce injury or injury could accelerate the senescence process, or both. The finding that increased p16 expression was seen in both atrophic and non-atrophic areas of the kidney biopsies of patients with deteriorating renal allograft function (Melk et al., 2005b) supports the idea that p16 expression is not the consequence of chronic histological, but rather precedes injury processes. Nevertheless, in the light of recent studies demonstrating that p16 expression could even be protective against fibrogenesis (see above) (Wolstein et al., 2010), more work needs to be done to elucidate the contribution of senescence mechanisms to chronic histological damage in renal allografts.
In conclusion, this review illustrates a central place of senescent pathways in renal disease, both in native kidneys and in renal allografts. Independent of chronological age, many disease processes lead to activation of senescent pathways and thus a state of “accelerated senescence.” Most studies were however performed in animal models, and validation in a human setting is necessary. Although the insight in the causes of replicative senescence in renal tissue is improving, the consequences of accelerated senescence on renal morphology and function are not that clear. It remains largely unanswered whether cellular senescence is a protective phenomenon or a damaging process. Whether cellular senescence plays an active or bystander role in fibrogenesis and atrophy of renal tissue has to be investigated.
The author reports no conflicts of interest.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(56):65-75, January 2011.]