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The osteoprotegerin/tumor necrosis factor related apoptosis-inducing ligand axis in the kidney

Candido, Riccardo

Current Opinion in Nephrology and Hypertension: January 2014 - Volume 23 - Issue 1 - p 69–74
doi: 10.1097/01.mnh.0000437611.42417.7a
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Purpose of review Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine belonging to the TNF superfamily. TRAIL may modulate cell survival and proliferation through interaction with two different receptors, TRAIL-R1 and TRAIL-R2. The actions of TRAIL are regulated by three decoy receptors, TRAIL-R3, TRAIL-R4 and osteoprotegerin (OPG). There is evidence that both TRAIL and OPG are expressed by renal cells. The OPG/TRAIL axis has been recently linked to the pathogenesis of renal damage and, in particular, diabetic nephropathy.

Recent findings In patients with kidney diseases, serum TRAIL and OPG levels are increased in parallel and are significantly associated with each other. In diabetic nephropathy, the renal expression of TRAIL and OPG is elevated, and in tubular cells proinflammatory cytokines enhance TRAIL expression. Additionally, a high-glucose microenvironment sensitizes tubular cells to apoptosis induced by TRAIL, whereas OPG counteracts the actions of TRAIL in cultured cells.

Summary It seems that the expression and levels of TRAIL and OPG at serum and kidney levels are crucial for the pathogenesis of kidney diseases, and in particular diabetic nephropathy. Although further studies are necessary to clarify the exact role of the OPG/TRAIL axis in the kidney, this system seems to hold promise to provide therapeutic approaches for the management of renal damage.

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Diabetes Centre, A.S.S. 1 Triestina, Trieste, Italy

Correspondence to Riccardo Candido, Diabetes Centre, A.S.S. 1 Triestina, Via G. Puccini 48/50, 34148 Trieste, Italy. Tel: +39 040 3995962; fax: +39 040 281455; e-mail:

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was originally identified by two independent groups and characterized as a member of the TNF family of death-inducing ligands [1,2]. TRAIL is a type II transmembrane protein of about 33–35 kD, which can be cleaved from the cell surface to form a soluble ligand that retains biological activity [3]. In the last few years, TRAIL has received particular attention because both full-length membrane-expressed TRAIL and the soluble ligand can rapidly induce apoptosis in a wide variety of human cancers [1], showing minimal or absent toxicity on normal cells. TRAIL was identified as a potential tumor-specific cancer therapeutic. TRAIL is normally expressed in many human tissues suggesting that it must not be cytotoxic to most tissues in vivo under normal physiological conditions [4]. However, when normal cells are immersed in an inflammatory environment, data from knockout mice suggest that TRAIL may induce parenchymal cell apoptosis [5]. Two additional alternative splice variants of TRAIL in human cells lacking either exon 3 (TRAIL-β) or exons 2 and 3 (TRAIL-γ) have been described [6]. The lack of apoptotic activity in both isoforms and an alternative splicing in response to cytokine stimulation add complexity to the system [7].

One of the system particularities is the multiple set of TRAIL receptors. In fact, TRAIL can bind five different receptors found on a variety of cell types: four membrane-bound and one soluble receptor [8] (Fig. 1). Two of these membrane receptors, TRAIL-R1/death receptor 4 (DR4) and TRAIL-R2/death receptor 5 (DR5), act as agonistic receptors, containing a cytoplasmatic death domain through which TRAIL can transmit an apoptotic signal. The other two membrane receptors, TRAIL-R3/decoy receptor 1 (DcR1) and TRAIL-R4/decoy receptor 2 (DcR2), can also bind TRAIL, but may act as antagonistic receptors, lacking the death domain. In addition to these four transmembrane receptors, a fifth soluble antagonistic receptor, osteoprotegerin (OPG), has been identified [9]. Unlike other members of the TNF-receptor superfamily, OPG lacks transmembrane and cytoplasmic domains and is secreted as a soluble protein [10]. OPG is produced by a variety of tissues including the cardiovascular system, lung, intestine, stomach, kidney and bone, as well as hematopoietic and immune cells [11,12]. OPG, initially described as a bone remodeling regulator based on its ability to block receptor activator of nuclear factor κB ligand (RANKL)-stimulated osteoclast formation, also interacts with TRAIL [9]. Although it has been suggested that the binding of TRAIL to OPG is weak at physiological temperature as compared with the binding of TRAIL to transmembrane receptors [13], more recent studies have underlined the biological relevance of OPG/TRAIL interactions in different in-vitro and in-vivo studies [10,14]. In this respect, there are data suggesting that TRAIL and its soluble decoy receptor OPG may be involved in the pathogenesis of cardiovascular disease [15–17,18▪▪,19], and in the development of both type 1 and type 2 diabetes [20,21,22▪] and its complications [15,18▪▪,23].



Box 1

Box 1

As there is evidence that TRAIL and OPG are normally expressed in the kidney, this review will examine the potential physiopathological role of the OPG/TRAIL axis in the kidney.

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TRAIL has been studied mostly for its potent tumor cell-killing activity [24]. Different combinations of TRAIL and chemotherapeutic drugs or the use of agonistic anti-TRAIL-R1 or R2 antibodies show promising results in the treatment of renal carcinoma [25,26]. More recently, eradication of metastatic renal cell carcinoma after adenovirus-encoded TRAIL/CpG immunotherapy in mice has been demonstrated [27▪]. Consistent with its role in tumor surveillance, TRAIL expression has been found to be lower in renal tumors with poor prognosis than in normal kidney and, conversely, TRAIL-R1 expression is higher in good prognosis tumors [28].

There is evidence that TRAIL has also nonapoptotic functions, such as prosurvival and proliferative effects [29,30]. Tissue distribution of TRAIL and its receptors in normal animal and human kidneys showed that TRAIL is expressed only in convoluted tubules [31]. TRAIL-R1 has a similar pattern of expression to TRAIL, whereas TRAIL-R2 is additionally expressed in Henle's loop [4]. TRAIL-R3 expression was not detected in the normal kidney, and there are no reports regarding renal tissue expression of TRAIL-R4.

No expression of TRAIL and its receptors was found in glomeruli or the renal vasculature [4]. TRAIL, TRAIL-R1 and TRAIL-R2 expression were relatively low in the kidney compared with some other tissues, such as the liver. In addition, no kidney disorder has been reported in TRAIL knockout mice, suggesting that TRAIL is not required for normal kidney development and physiology [32].

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Recent observations suggest that TRAIL may be involved in the pathogenesis of diabetic nephropathy. Lorz et al. [31] demonstrated that TRAIL mRNA was upregulated in the tubulointerstitium of patients with diabetic nephropathy and that proximal tubular TRAIL expression, as assessed by immunohistochemistry, was higher in diabetic kidney when compared with controls and was associated with clinical and histologic severity of the disease. In-vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. The same authors observed that a high-glucose medium, characteristic of diabetes, sensitized tubular cells and podocytes to the proapoptotic effects of TRAIL suggesting that TRAIL-induced cell death could play an important role in the progression of diabetic nephropathy [31]. Interestingly, in diabetic nephropathy, de-novo expression of glomerular TRAIL has also been observed [31].

The role of inflammatory cytokines, such as TNF, interferon (IFN)-γ and macrophage migration inhibitory factor, in the induction of TRAIL expression in tubular cells and podocytes in diabetic nephropathy has also been confirmed more recently by other studies [33].

In a time course experimental study, Chen et al.[34] have shown that when compared with the control group, renal TRAIL expression levels in diabetic animals were significantly lower before the 12th week after induction of diabetes, and then significantly higher in the 16th week. In addition, the same authors observed that in the early stage of diabetic nephropathy, treatment with valsartan may upregulate the expression of TRAIL, thus suggesting a possible protective role of TRAIL in the kidney [34].

Serum concentrations of TRAIL are significantly elevated in diabetic patients with microalbuminuria and macroalbuminuria when compared with normoalbuminuric patients [35]. In addition, serum TRAIL and OPG levels are increased in parallel and are significantly associated with each other.

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Although there is little information on the role of TRAIL in renal disease in addition to diabetic nephropathy, there is evidence that TRAIL may also be involved in the pathogenesis of other renal diseases. Eichler et al.[36] showed that TRAIL may be involved in renal tubular and glomerular injury induced by exposure to toxic metals. In addition, there are data suggesting that TRAIL, DR4 and DR5 are upregulated in proximal and distal tubules of patients with proliferative lupus nephritis [37]. In the same article, expression of TRAIL, DR4 and DR5 on primary proximal tubular epithelial cells (PTECs) was induced, in vitro, by TNF-α and IFN-γ [37]. Functionally, TRAIL did not induce apoptosis but rather enhanced the proliferation of PTECs through the activation of PI3 kinase/AKT and ERK1/2, increased interleukin-8 production and upregulated ICAM-1 expression. These data demonstrate that cytokine-induced upregulation of TRAIL, DR4 and DR5 in tubules from patients with proliferative lupus nephritis may play a protective role by enhancing PTECs survival while at the same time exerting a proinflammatory effect that may contribute to local inflammation and injury. TRAIL mRNA is also upregulated in peripheral blood mononuclear cells in patients with minimal-change nephrotic syndrome during the nephrosis phase [38]. It is not yet established whether this change represents an epiphenomenon, or it may provide a potential explanation for the altered T-cell function in minimal-change nephrotic syndrome.

The expression of TRAIL, DR4 and DR5, and serum sTRAIL levels are also markedly upregulated among renal transplant patients suggesting that TRAIL and its receptors may participate in renal graft rejection [39].

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Endogenous OPG expression is localized within the smooth muscle layer (media) of the aortic and renal arteries, suggesting a role for OPG in maintaining normal structure in larger renal arteries [40]. In contrast to the limited information on TRAIL in kidney disease, there is ample evidence that OPG is increased in the serum of patients with renal dysfunction [41–43], particularly in patients with diabetic nephropathy [44,45]. Data from the Framingham Offspring cohort showed that serum levels of OPG were increased in chronic kidney disease (CKD) patients versus those without CKD [46]. In subjects with type 1 diabetes and nephropathy, plasma OPG level was shown to be a powerful and independent predictor of progression to end-stage renal disease and cardiovascular and all-cause mortality [47]. These observations have been recently confirmed by Gordin et al.[48▪] who showed that OPG concentrations were elevated only in type 1 diabetic patients with macroalbuminuria and/or renal impairment, when compared with patients without overt kidney disease. Furthermore, in this population, serum OPG was an independent predictor of cardiovascular complications [48▪]. Indeed, it has been shown that plasma OPG is elevated in type 1 diabetes patients with nephropathy and gradually increases with the severity of the kidney injury [49▪▪]. This finding supports the growing concept that OPG may act as an important regulatory molecule in microangiopathy and, particularly, that it may be involved in the development of nephropathy in type 1 diabetes. Serum concentrations of OPG are also significantly elevated in patients with type 2 diabetes with microalbuminuria and macroalbuminuria as compared with normoalbuminuric patients [35]. Using multivariate stepwise regression analysis, serum OPG was found to be an independent factor associated with the severity of diabetic nephropathy. Moreover, in patients with diabetes mellitus who had received a kidney transplant, circulating OPG levels have been recently shown to predict long-term patient survival and cardiovascular mortality [50].

Increased OPG serum levels are associated with increased coronary artery and aorta calcification and behave as an independent predictor of cardiovascular death in hemodialysis patients, raising concerns about a potentially deleterious effect of OPG [41,42]. It has been proposed that increased OPG may contribute to endothelial dysfunction and vascular damage, based on cell culture and experimental in-vivo studies that showed interference with actions of RANKL or TRAIL [16].

Microarray studies have shown upregulation of OPG mRNA levels in kidney samples from patients with diabetes mellitus and chronic renal injury [31,51]. In addition, it has been demonstrated that OPG interferes with TRAIL-induced actions on cultured renal tubular cells and improves cell survival, suggesting that the interplay between TRAIL and OPG might be one of the pathways for OPG to modulate diabetic tissue injury [31]. The contribution of OPG in vivo will probably depend on the relative local tissue levels of both molecules in the cell microenvironment, as is the case for other cytokine/soluble receptor systems.

Although there is considerable information on the role of OPG in diabetic nephropathy, there is some evidence that OPG may be involved also in the pathogenesis of other renal diseases. Higher levels of urinary OPG have been observed in patients with lupus nephritis. Furthermore, there is evidence that, in these patients, OPG urinary levels positively correlate with renal involvement with reasonable sensitivity, specificity, and predictive values to detect lupus nephritis [52]. In addition, it has been observed that in patients with chronic kidney disease there is a strong relationship between serum OPG levels and arterial stiffness [53]. Moreover, in a large cohort of kidney transplant patients with long-term follow-up, a clear association between OPG levels, doubling of serum creatinine or graft loss has been demonstrated [54▪].

The mechanisms by which OPG is increased in patients with renal damage are still unclear. The retention of peptides like OPG associated with renal impairment may provide part of the explanation. Nevertheless, as inflammation is elevated at systemic and local level in patients with renal injury, it may be that inflammation may also drive the expression of OPG, which through the induction of proliferation, inflammation and fibrogenesis may contribute to the pathogenesis of kidney damage. Thus, the existing data suggest that OPG may be an activator/regulator of kidney damage rather than merely an inactive marker of renal disease.

Further studies are necessary to investigate the role of OPG in the pathogenesis of kidney injury.

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In this review, we have delineated possible renal physiological and pathological functions of TRAIL and OPG molecules (Table 1). In particular, animals and human studies have demonstrated an increased expression of TRAIL and OPG in the diabetic kidney and other chronic kidney diseases. Although cell culture data point to a role for TRAIL in regulating tubular cell death, in cooperation with cytokines and glucose from the cell microenvironment, in-vitro and in-vivo evidence that support this hypothesis is still lacking. It seems that the expression and levels of TRAIL and OPG at the kidney level are crucial for the interaction of these two components. More knowledge about their interplay are needed. Although further studies are necessary to clarify the role of the OPG/TRAIL axis in the pathogenesis of kidney diseases, this system seems to hold promise in providing new therapeutic approaches for the management of renal injury and, in particular, diabetic nephropathy.

Table 1

Table 1

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Conflicts of interest

R.C. has received lecturing fees or has been a member of scientific advisory boards for Abbott Diabetes Care, Novartis, Roche Diagnostics, Johnson & Johnson Medical, Eli Lilly Italy, Astra Zeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Chiesi Farmaceutici, Sigma-Tau, ForFarma, Novo Nordisk, Rottapharm.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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This article shows that OPG concentrations are elevated only in type 1 diabetes patients with macroalbuminuria and/or renal impairment and that in these populations serum OPG is an independent predictor of cardiovascular complications.

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This article demonstrates that plasma values of OPG are elevated in type 1 diabetes patients with nephropathy and gradually increased with the severity, so there is an association between plasma OPG levels and the presence and severity of diabetic nephropathy. This finding supports the growing concept that OPG may act as an important regulatory molecule in angiopathy and, particularly, that it may be involved in the development of nephropathy in type 1 diabetes.

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diabetic nephropathy; kidney; osteoprotegerin; TRAIL

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