Background: Pentosidine, an advanced glycation end product, accumulates in plasma proteins of uremic patients. Its fate is, however, yet to be fully understood. Methods: Three cell lines, JTC-12 (proximal tubular cells), MDCK (distal tubular cells), and BALB3T3 (nonrenal cells), were cultured in a double chamber system and were exposed to uremic serum, and the contents of protein-linked pentosidine derived from uremic sera were determined in each medium by HPLC assay. The presence of pentosidine in the cytoplasm of these cells was assessed by immunoperoxidase staining. Results: When the apical cell membrane was exposed to uremic serum (fortified in the upper chamber), the contents of protein-linked pentosidine in the upper medium decreased by up to 30% after 24- and 48-hour incubations of JTC-12 cells but not of other cells. On the other hand, the contents of protein-linked pentosidine in the lower medium did not change. By contrast, exposure of the basolateral cell membrane of the three cell lines to uremic serum (fortified in the lower chamber) did not change the contents of protein-linked pentosidine both in the upper and lower medium after a 24-hour incubation. Pentosidine was detected immunohistochemically in the cytoplasm of JTC-12 cells, but not of BALB3T3 and MDCK cells, the apical membranes of which were exposed to uremic sera for 8 h. The immunoreaction disappeared 48 h after exposure. Pentosidine was not detected in the cytoplasm of JTC-12 cells, the basolateral membranes of which were exposed to uremic sera. The relevance of the in vitro results to humans was demonstrated by immunohistochemical studies in normal human kidney tissues showing that pentosidine was identified in the proximal renal tubules. Conclusion: These results suggest that the proximal tubular cells play a role in the disposal of plasma pentosidine.

Keywords:
Advanced glycation end product, Disposal, pentosidine, JTC-12-cell, Proximal tubule
1.
Sell DR, Monnier VM: Structure elucidation of a senescence cross-link from human extracellular matrix. J Biol Chem 1989;264:21597–21602.
2.
Miyata T, Taneda S, Kawai R, et al: Identification of pentosidine as a native structure for advanced glycation end products in β2-microglobulin-containing amyloid fibrils in patients with dialysis-related amyloidosis. Proc Natl Acad Sci USA 1996;93:2353–2358.
3.
Miyata T, Ueda Y, Shinzato T, et al: Accumulation of albumin-linked and free-form pentosidine in the circulation of uremic patients with end-stage renal failure: Renal implications in the pathophysiology of pentosidine. J Am Soc Nephrol 1996:7:1198–1206.
4.
Miyata T, Ueda Y, Yoshida A, et al: Clearance of pentosidine, an advanced glycation end product, by different modalities of renal replacement therapy. Kidney Int 1997;51:880–887.
5.
Miyata T, Ueda Y, Yasuda Y, et al: Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycation end product: Carbonyl stress in uremia. J Am Soc Nephrol 1998;9:2349–2356.
6.
Miyata T, van Ypersele de Strihou C, Kurokawa K, et al: Alterations in nonenzymatic biochemistry in uremia: Origin and significance of ‘carbonyl stress’ in long-term uremic complications. Kidney Int 1999;55:389–399.
7.
Miyata T, Oda O, Inagi R, et al: β2-Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyloidosis. J Clin Invest 1993;92:1243–1252.
8.
Miyata T, Inagi R, Iida Y, et al: Involvement of β2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. J Clin Invest 1994;93:521–528.
9.
Makita Z, Radoff S, Rayfield EJ, et al: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 1991;325:836–842.
10.
Miyata T, Ishikawa S, Asahi K, et al: 2-Isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195) treatment inhibits the development of intimal thickening after balloon injury of rat carotid artery: Role of glycoxidation and lipoxidation reactions in vascular tissue damage. FEBS Lett 1999;445:202–206.
11.
Gugliucci A, Bendayan M: Renal fate of circulating advanced glycated end products (AGE): Evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells. Diabetologia 1996;39:149–160.
12.
Reddy S, Bichler J, Wells-Knecht KJ, et al: N(epsilon)-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry 1995;34:10872–10878.
13.
Bendayan M, Londono I: Reabsorption of native and glycated albumin by renal proximal tubular epithelial cells. Am J Physiol 1996;271:F261–F268.
14.
Miyata T, Ueda Y, Horie K, et al: Renal catabolism of advanced glycation end products: The fate of pentosidine. Kidney Int 1998;53:416–422.
15.
Takaoka T, Katsuta H, Endo M, et al: Establishment of a cell strain, JTC-12, from cynomolgus monkey kidney tissue. Jpn J Exp Med 1962;32:351–368.
16.
Aaronson SA, Todaro GJ: Development of 3T3-like lines from Balb/c mouse embryo culture: Transformation susceptibility to SV40. J Cell Physiol 1968;72:141–148.
17.
Gaush CR, Hard WL, Smith TF: Characterization of an established line of canine kidney cells (MDCK). Proc Soc Exp Biol Med 1966;122:931–935.
18.
Horie K, Miyata T, Maeda K, et al: Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. J Clin Invest 1997;100:2995–3004.
19.
Sheibani K, Battifora H, Burke JS, et al: Leu-M1 antigen in human neoplasms: An immunohistologic study of 400 cases. Am J Surg Pathol 1986;10:227–236.
20.
Comper WD, Glasgow EF: Charge selectivity in kidney ultrafiltration. Kidney Int 1995;47:1242–1251.
21.
Londono I, Ghitescu L, Bendayan M: Glomerular handling of circulating glycated albumin in the normal mouse kidney. Am J Physiol 1995;268:F913–F921.
22.
Oken DE, Cotes SC, Mende CW: Micropuncture study of tubular transport of albumin in rats with aminonucleoside nephrosis. Kidney Int 1972;1:3–11.
23.
Park CH, Maack T: Albumin absorption and catabolism by isolated perfused proximal convoluted tubules of the rabbit. J Clin Invest 1984;73:767–777.
24.
Schwegler JS, Heppelmann B, Mildenberger S, et al: Receptor-mediated endocytosis of albumin in cultured opossum kidney cells: A model for proximal tubular protein reabsorption. Pflügers Arch 1991;418:383–392.
25.
Schnitzer JE, Oh P: Albondin-mediated capillary permeability to albumin: Differential role of receptors in endothelial transcytosis and endocytosis of native and modified albumins. J Biol Chem 1994;269:6072–6082.
26.
Gekle M, Mildenberger S, Freudinger R, et al: Functional characterization of albumin binding to the apical membrane of OK cells. Am J Physiol 1996;271:F286–F291.
27.
Gekle M, Mildenberger S, Freudinger R, et al: Endosomal alkalinization reduces Jmax and Km of albumin receptor-mediated endocytosis in OK cells. Am J Physiol 1995;268:F899–F906.
28.
Birn H, Fyfe JC, Jacobsen C, et al: Cubilin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest 2000;105:1353–1361.
29.
Zhai XY, Nielsen R, Birn H, et al: Cubilin- and megalin-mediated uptake of albumin in cultured proximal tubule cells of opossum kidney. Kidney Int 2000;58:1523–1533.
30.
Abel M, Ritthaler U, Zhang Y, et al: Expression of receptors for advanced glycosylated end-products in renal disease. Nephrol Dial Transplant 1995;10:1662–1667.
31.
Kislinger T, Fu C, Huber B, et al: N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 1999;274:31740–31749.
© 2002 S. Karger AG, Basel
2002
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