The Plasma Osteoprotegerin Level and Osteoprotegerin Expression in Renal Biopsy Tissue are Increased in Type 2 Diabetes with Nephropathy

Abstract

Objective: To investigate the plasma osteoprotegerin level and osteoprotegerin expression in renal biopsy tissue in type 2 diabetes with nephropathy.

Methods: Plasma osteoprotegerin level was measured by enzyme-linked immunoassay in 48 type 2 diabetes with normoalbuminuria, 48 patients with microalbuminuria, 44 patients with macroalbuminuria and 40 healthy persons. Part of diabetes patients with nephropathy were performed kidney biopsy by ultrasound guide. The osteoprotegerin expression in kidney biopsy tissue is examined by immunohistochemistry.

Results: The plasma osteoprotegerin levels were significantly elevated in patients with microalbuminuria (3.73±0.75 ng/l) and macroalbuminuria (4.68±0.82 ng/l) as compared with patients with normoalbuminuria (2.71±0.69 ng/l) and control subjects (2.11±0.42 ng/l). And the plasma osteoprotegerin level in macroalbuminuric group was also higher than that in microalbuminuria group. The plasma osteoprotegerin level had a positive correlation with the fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), glycohemoglobinA1c (HbA1C), high sensitive C-reactive protein (hsCRP) and log(UAER). Multivariate regression analysis revealed that plasma osteoprotegerin level was an independent factor associated with albuminuria in type 2 diabetes. The immunohistochemistry results showed that positive immunostaining for osteoprotegerin was observed in the renal tubule cells of biopsy and not in glomerulus, and the osteoprotegerin expression was higher in macroalbuminuria group than that in microalbuminuria group.

Conclusions: The plasma osteoprotegerin level and the osteoprotegerin expression in renal tubule cells of biopsy tissue were increased in nephropathy of type 2 diabetes. This finding supports the growing concept that osteoprotegerin may act as an important regulatory molecule in the angiopathy, and particularly, that it may be involved in the occurrence and development of nephropathy in type 2 diabetes.

Key words

Type 2 diabetes - osteoprotegerin - diabetic nephropathy

^* These authors contributed equally to this study and share first authorship.

• References

• 1 Tsuda E, Goto M, Mochizuki S et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 1997; 234: 137-142
• 2 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
• 3 Lee JE, Kim HJ, Moon SJ et al. Plasma osteoprotegerin is associated with vascular stiffness and the onset of new cardiovascular events in hemodialysis patients. Korean J Intern Med 2013; 28: 668-677
• 4 Olesen P, Nguyen K, Wogensen L et al. Calcification of human vascular smooth muscle cells: associations with osteoprotegerin expression and acceleration by high-dose insulin. Am J Physiol Heart Circ Physiol 2007; 292: H1058-H1064
• 5 Kim J, Song TJ, Yang SH et al. Plasma osteoprotegerin levels increase with the severity of cerebral artery atherosclerosis. Clin Biochem 2013; 46: 1036-1040
• 6 Giaginis C, Papadopouli A, Zira A et al. Correlation of plasma osteoprotegerin (OPG) and receptor activator of the nuclear factor κB ligand (RANKL) levels with clinical risk factors in patients with advanced carotid atherosclerosis. Med Sci Monit 2012; 18: CR597-CR604
• 7 Schoppet M, Al Fakhri N, Franke FE et al. Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappaB ligand in Monckeberg’s sclerosis and atherosclerosis. J Clin Endocrinol Metab 2004; 89: 4104-4112
• 8 Ghaffari S, Yaghoubi A, Baghernejad R et al. The value of plasma osteoprotegerin levels in patients with angina like chest pain undergoing diagnostic coronary angiography. Cardiol J 2013; 20: 261-267
• 9 Pedersen S, Mogelvang R, Bjerre M et al. Osteoprotegerin predicts long-term outcome in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Cardiology 2012; 123: 31-38
• 10 Augoulea A, Vrachnis N, Lambrinoudaki I et al. Osteoprotegerin as a marker of atherosclerosis in diabetic patients. Int J Endocrinol 2013; 182060
• 11 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
• 12 Wang ST, Xu JM, Wang M et al. Increased plasma osteoprotegerin concentrations in Type 1 diabetes with albuminuria. Clin Nephrol 2013; 79: 192-198
• 13 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
• 14 Xiang GD, Pu JH, Zhao LS et al. Association between plasma osteoprotegerin concentrations and urinary albumin excretion in type 2 diabetes. Diabet Med 2009; 26: 397-403
• 15 Levey AS, Coresh J, Greene T et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006; 145: 247-254
• 16 Golledge J, McCann M, Mangan S et al. Osteoprotegerin and osteopontin are expressed at high concentrations within symptomatic carotid atherosclerosis. Stroke 2004; 35: 1636-1641
• 17 Xiang GD, Sun HL, Zhao LS. Changes of osteoprotegerin before and after insulin therapy in type 1 diabetic patients. Diabetes Res Clin Pract 2007; 76: 199-206
• 18 Zhou S, Fang X, Xin H et al. Osteoprotegerin inhibits calcification of vascular smooth muscle cell via down regulation of the Notch1-RBP-Jκ/Msx2 signaling pathway. PLoS One 2013; 8: e68987
• 19 Malyankar UM, Scatena M, Suchland KL et al. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem 2000; 275: 20959-20962
• 20 Bucay N, Sarosi I, Dunstan CR et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-1268
• 21 O’Sullivan EP, Ashley DT, Davenport C et al. Osteoprotegerin is higher in peripheral arterial disease regardless of glycaemic status. Thromb Res 2010; 126: e423-e427
• 22 Jono S, Ikari Y, Shioi A et al. Plasma osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002; 106: 1192-1194
• 23 Hofbauer LC, Schoppet M. Osteoprotegerin: a link between osteoporosis and arterial calcification?. Lancet 2001; 358: 257-259
• 24 Dhore CR, Cleutjens JP, Lutgens E et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2001; 21: 1998-2003
• 25 Zhang J, Fu M, Myles D et al. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Lett 2002; 521: 180-184
• 26 Schoppet M, Kavurma MM, Hofbauer LC et al. Crystallizing nanoparticles derived from vascular smooth muscle cells contain the calcification inhibitor osteoprotegerin. Biochem Biophys Res Commun 2011; 407: 103-107
• 27 Benslimane-Ahmim Z, Poirier F, Delomenie C et al. Mechanistic study of the proangiogenic effect of osteoprotegerin. Angiogenesis 2013; 16: 575-593
• 28 Knudsen ST, Foss CH, Poulsen PL et al. Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications. Eur J Endocrinol 2003; 149: 39-42
• 29 Kim SM, Leet J, Ryu OH et al. Serum osteoprotegerin levels are associated with inflammation and pulse wave velocity. Clin Endocrinol 2005; 63: 594-598
• 30 Kiechl S, Schett G, Wenning G et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004; 109: 2175-2180
• 31 Rhee EJ, Lee WY, Kim SY et al. Relationship of serum osteoprotegerin levels with coronary artery disease severity, left ventricular hypertrophy and C-reactive protein. Clin Sci 2005; 108: 237-243
• 32 Yaturu S, Rains J, Jain SK. Relationship of elevated osteoprotegerin with insulin resistance, CRP, and TNF-a levels in men with type 2 diabetes. Cytokine 2008; 44: 168-171
• 33 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