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 .
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 . 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 . 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 . 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 . 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 .
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 .
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.
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.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3:673–682.
2. Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271:12687–12690.
3. Duiker EW, Mom CH, de Jong S, et al. The clinical trial of TRAIL
. Eur J Cancer 2006; 42:2233–2240.
4. Spierings DC, de Vries EG, Vellenga E, et al. Tissue distribution of the death ligand TRAIL
and its receptors. J Histochem Cytochem 2004; 52:821–831.
5. Zheng SJ, Wang P, Tsabary G, Chen YH. Critical roles of TRAIL
in hepatic cell death and hepatic inflammation. J Clin Invest 2004; 113:58–64.
6. Krieg A, Krieg T, Wenzel M, et al. TRAIL
-beta and TRAIL
-gamma: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL
) without apoptotic potential. Br J Cancer 2003; 88:918–927.
7. Kamachi M, Aramaki T, Tanimura S, et al. Activation of protein phosphatase causes alternative splicing of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL
): potential effect on immune surveillance. Biochem Biophys Res Commun 2007; 360:280–285.
8. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998; 281:1305–1308.
9. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin
is a receptor for the cytotoxic ligand TRAIL
. J Biol Chem 1998; 273:14363–14367.
10. Corallini F, Rimondi E, Secchiero P. TRAIL
: a role in endothelial physiopathology? Front Biosci 2008; 13:135–147.
11. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin
: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89:309–319.
12. Tan KB, Harrop J, Reddy M, et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and nonhematopoietic cells. Gene 1997; 204:35–46.
13. Truneh A, Sharma S, Silverman C, et al. Temperature-sensitive differential affinity of TRAIL
for its receptors. DR5 is the highest affinity receptor. J Biol Chem 2000; 275:23319–23325.
14. Miyashita T, Kawakami A, Nakashima T, et al. Osteoprotegerin
(OPG) acts as an endogenous decoy receptor in tumour necrosis factor-related apoptosis-inducing ligand (TRAIL
)-mediated apoptosis of fibroblast-like synovial cells. Clin Exp Immunol 2004; 137:430–436.
15. Secchiero P, Candido R, Corallini F, et al. Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice. Circulation 2006; 114:1522–1530.
16. Secchiero P, Corallini F, Pandolfi A, et al. An increased osteoprotegerin
serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction. Am J Pathol 2006; 169:2236–2244.
17. Candido R, Toffoli B, Corallini F, et al. Human full-length osteoprotegerin
induces the proliferation of rodent vascular smooth muscle cells both in vitro and in vivo. J Vasc Res 2010; 47:252–261.
18▪▪. Toffoli B, Bernardi S, Candido R, et al. TRAIL
shows potential cardioprotective activity. Invest New Drugs 2012; 30:1257–1260.
This is the first experimental study demonstrating that therapeutic administration of TRAIL might have a cardioprotective effect.
19. Bernardi S, Milani D, Fabris B, et al. TRAIL
as biomarker and potential therapeutic tool for cardiovascular diseases. Curr Drug Targets 2012; 13:1215–1221.
20. Toffoli B, Bernardi S, Candido R, et al. Osteoprotegerin
induces morphological and functional alterations in mouse pancreatic islets. Mol Cell Endocrinol 2011; 331:136–142.
21. Bernardi S, Norcio A, Toffoli B, et al. Potential role of TRAIL
in the management of autoimmune diabetes mellitus. Curr Pharm Des 2012; 18:5759–5765.
22▪. Bernardi S, Zauli G, Tikellis C, et al. TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation. Clin Sci 2012; 123:547–555.
This article sheds light on the possible antiadipogenic and anti-inflammatory effects of TRAIL and opens new therapeutic possibilities against obesity, systemic inflammation and type 2 diabetes.
23. Secchiero P, Perri P, Melloni E, et al. Decreased levels of soluble TNF-related apoptosis-inducing ligand (TRAIL
) in the conjunctival sac fluid of patients with diabetes affected by proliferative retinopathy. Diabet Med 2011; 28:1277–1278.
24. Bernardi S, Secchiero P, Zauli G. State of art and recent developments of anticancer strategies based on TRAIL
. Recent Pat Anticancer Drug Discov 2012; 7:207–217.
25. Wu XX, Ogawa O, Kakehi Y. TRAIL
and chemotherapeutic drugs in cancer therapy. Vitam Horm 2004; 67:365–383.
26. Marini P. Drug evaluation: lexatumumab, an intravenous human agonistic mAb targeting TRAIL
receptor 2. Curr Opin Mol Ther 2006; 8:539–546.
27▪. Norian LA, Kresowik TP, Rosevear HM, et al. Eradication of metastatic renal cell carcinoma after adenovirus-encoded TNF-related apoptosis-inducing ligand (TRAIL
)/CpG immunotherapy. PLoS One 2012; 7:e31085.
This review demonstrates eradication of metastatic renal cell carcinoma after adenovirus-encoded TRAIL/CpG immunotherapy in mice. A similar approach may prove beneficial for patients with metastatic renal cell carcinoma.
28. Takamizawa S, Okamoto S, Bishop W, et al. Differential apoptosis gene expression in pediatric tumors of the kidney
. J Pediatr Surg 2000; 35:390–395.
29. Di Pietro R, Zauli G. Emerging nonapoptotic functions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL
)/Apo2L. J Cell Physiol 2004; 201:331–340.
30. Secchiero P, Zerbinati C, Rimondi E, et al. TRAIL
promotes the survival, migration and proliferation of vascular smooth muscle cells. Cell Mol Life Sci 2004; 61:1965–1974.
31. Lorz C, Benito-Martin A, Boucherot A, et al. The death ligand TRAIL
in diabetic nephropathy
. J Am Soc Nephrol 2008; 19:904–914.
32. Cretney E, Takeda K, Yagita H, et al. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002; 168:1356–1361.
33. Sanchez-Nino MD, Sanz AB, Ihalmo P, Lassila M, et al. The MIF receptor CD74 in diabetic podocyte injury. J Am Soc Nephrol 2009; 20:353–362.
34. Chen B, Zhang Y, Liu G, Guan GJ, et al. Effects of valsartan, mycophenolate mofetil and their combined application on TRAIL
and nuclear factor-kappaB expression in the kidneys of diabetic rats. [Chinese]. Zhonghua Yi Xue Za Zhi 2008; 88:540–545.
35. Chang YH, Lin KD, He SR, et al. Serum osteoprotegerin
and tumor necrosis factor related apoptosis inducing-ligand (TRAIL
) are elevated in type 2 diabetic patients with albuminuria and serum osteoprotegerin
is independently associated with the severity of diabetic nephropathy
. Metabolism 2011; 60:1064–1069.
36. Eichler T, Ma Q, Kelly C, et al. Single and combination toxic metal exposures induce apoptosis in cultured murine podocytes exclusively via the extrinsic caspase 8 pathway. Toxicol Sci 2006; 90:392–399.
37. Nguyen V, Cudrici C, Zernetkina V, et al. TRAIL
, DR4 and DR5 are upregulated in kidneys from patients with lupus nephritis and exert proliferative and proinflammatory effects. Clin Immunol 2009; 132:32–42.
38. Okuyama S, Komatsuda A, Wakui H, et al. Up-regulation of TRAIL
mRNA expression in peripheral blood mononuclear cells from patients with minimal-change nephrotic syndrome. Nephrol Dial Transplant 2005; 20:539–544.
39. Song CJ, Liu XS, Zhu Y, et al. Expression of TRAIL
, DR4, and DR5 in kidney
and serum from patients receiving renal transplantation. Transplant Proc 2004; 36:1340–1343.
40. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin
-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12:1260–1268.
41. Nitta K, Akiba T, Uchida K, et al. The progression of vascular calcification and serum osteoprotegerin
levels in patients on long-term hemodialysis. Am J Kidney
Dis 2003; 42:303–309.
42. Avbersek-Luznik I, Malesic I, Rus I, Marc J. Increased levels of osteoprotegerin
in hemodialysis patients. Clin Chem Lab Med 2002; 40:1019–1023.
43. Kazama JJ, Shigematsu T, Yano K, et al. Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin
) in patients with chronic renal failure. Am J Kidney
Dis 2002; 39:525–532.
44. Rasmussen LM, Tarnow L, Hansen TK, et al. Plasma osteoprotegerin
levels are associated with glycaemic status, systolic blood pressure, kidney
function and cardiovascular morbidity in type 1 diabetic patients. Eur J Endocrinol 2006; 154:75–81.
45. Doi S, Yorioka N, Masaki T, et al. Increased serum osteoprotegerin
level in older and diabetic hemodialysis patients. Ther Apher Dial 2004; 8:335–339.
46. Upadhyay A, Larson MG, Guo CY, et al. Inflammation, kidney
function and albuminuria in the Framingham Offspring cohort. Nephrol Dial Transplant 2011; 26:920–926.
47. Jorsal A, Tarnow L, Flyvbjerg A, et al. Plasma osteoprotegerin
levels predict cardiovascular and all-cause mortality and deterioration of kidney
function in type 1 diabetic patients with nephropathy. Diabetologia 2008; 51:2100–2107.
48▪. Gordin D, Soro-Paavonen A, Thomas MC, et al. Osteoprotegerin
is an independent predictor of vascular events in finnish adults with type 1 diabetes. Diabetes Care 2013; 36:1827–1833.
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.
49▪▪. Wang ST, Xu JM, Wang M, et al. Increased plasma osteoprotegerin
concentrations in Type 1 diabetes with albuminuria. Clin Nephrol 2013; 79:192–198.
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.
50. Anand DV, Lahiri A, Lim E, et al. The relationship between plasma osteoprotegerin
levels and coronary artery calcification in uncomplicated type 2 diabetic subjects. J Am Coll Cardiol 2006; 47:1850–1857.
51. Benito-Martin A, Ucero AC, Santamaria B, et al. Transcriptomics illustrate a deadly TRAIL
to diabetic nephropathy
[Spanish]. Nefrologia 2009; 29:13–19.
52. El-Shehaby A, Darweesh H, El-Khatib M, et al. Correlations of urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin
(OPG), monocyte chemoattractant protein-1 (MCP-1), and IL-8 with lupus nephritis. J Clin Immunol 2011; 31:848–856.
53. Scialla JJ, Leonard MB, Townsend RR, et al. Correlates of osteoprotegerin
and association with aortic pulse wave velocity in patients with chronic kidney
disease. Clin J Am Soc Nephrol 2011; 6:2612–2619.
54▪. Svensson M, Dahle DO, Mjoen G, et al. Osteoprotegerin
as a predictor of renal and cardiovascular outcomes in renal transplant recipients: follow-up data from the ALERT study. Nephrol Dial Transplant 2012; 27:2571–2575.