Chronic tubulointerstitial injury (CTI), commonly a sequel to chronic glomerulonephritis (CGN), is associated with the proliferation of new blood vessels. Angiogenesis is an essential process in chronic inflammation, and is controlled by a number of angiogenic factors including thymidine phosphorylase (TP). Knowledge of TP in renal disease is still rudimentary, and its role in CGN has not been explored. We analyzed the expression of TP by RTPCR, immunohistology and in situ hybridization in 20 human kidneys with CGN. To evaluate the degree of angiogenesis, we counted the microvessel density (MVD). MVD was significantly higher in all categories of CGN, between 19.7 ± 7.7 and 58.9 ± 7.5, compared to control value, 12.7 ± 5.0 (p< 0.05). MVD was increased in areas of abundant mononuclear cell infiltration with minimal interstitial fibrosis, and decreased or absent in areas of marked fibrosis. There was a significant correlation between MVD and interstitial fibrosis (p < 0.0001). TP mRNA was upregulated for all categories of CGN. TP was strongly expressed by mononuclear inflammatory cells and in most atrophic tubules. Each MVD and interstitial volume was significantly correlated with both the number of TP+ mononuclear cells and TP+ tubular cells, respectively (p < 0.0001). We have demonstrated an upregulation of TP and increase in MVD in areas of CTI in a variety of CGN. The up-regulation of TP may contribute to angiogenesis, which may play a critical role in the progression of interstitial fibrosis in CGN.

1.
Bohle A, Gise HV, Mackensen-Haen S, Stark-Jakob B: The obliteration of the postglomerular capillaries and its influence upon the function of both glomeruli and tubuli. Klin Wochenschr 1981;59:1043–1051.
2.
Seron D, Alexopoulos E, Raftery MJ, et al: Number of interstitial capillary cross-sections assessed by monoclonal antibodies: relation to interstitial damage. Nephrol Dial Transplant 1990;5:889–893.
3.
Mackensen-Haen S, Bohle A, Christensen J, et al: The consequences for renal function of widening of the interstitium and changes in the tubular epithelium of the renal cortex and outer medulla in various renal diseases. Clin Nephrol 1992;37:70–77.
4.
Møller JC, Skriver E, Olsen S, Maunsbach AB: Ultrastructural analysis of human proximal tubules and cortical interstitium in chronic renal disease (hydronephrosis). Virchows Arch 1984;402:209–237.
5.
Møller JC, Jørgensen TM, Mortensen J: Proximal tubular atrophy: qualitative and quantitative structural changes in chronic obstructive nephropathy in the pig. Cell Tissue Res 1986;244:479–491.
6.
Truong LD, Farhood A, Tasby J, Gillum D: Experimental chronic renal ischemia: Morphologic and immunologic studies. Kidney Int 1992;41:1676–1689.
7.
Eddy AA: Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 1996;7:2495–2508.
8.
Iltzsch MH, el Kouni MH, Cha S: Kinetic studies of thymidine phosphorylase from mouse liver. Biochemistry 1985;19:6799–6807.
9.
Brown NS, Bicknell R: Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis. Biochem J 1998;334:1–8.
10.
Miyazono K, Okabe T, Urabe A, et al: Purification and properties of an endothelial cell growth factor from human platelets. J Biol Chem 1987;262:4098–4103.
11.
Ishikawa F, Miyazono K, Hellman U, et al: Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 1989;338:557–562.
12.
Takahashi Y, Bucana CD, Liu W, et al: Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer Inst 1996;88:1146–1151.
13.
Waguri-Nagaya Y, Otsuka T, Sugimura I, et al: Synovial inflammation and hyperplasia induced by gliostatin/platelet-derived endothelial cell growth factor in rabbit knees. Rheumatol Int 2000;20:13–19.
14.
Folkman J: What is the role of thymidine phosphorylase in tumor angiogenesis. J Natl Cancer Inst 1996;88:1091–1092.
15.
Yoshimura A, Kuwazuru Y, Furukawa T, et al: Purification and tissue distribution of human thymidine phosphorylase: high expression in lymphocytes, reticulocytes and tumors. Biochem Biophys Acta 1990;1034:107–113.
16.
Folkman J, Shing Y: Angiogenesis. J Biol Chem 1992;267:10931–10934.
17.
Fox SB, Moghaddam A, Westwood M, Turley H, et al: Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: an immunohistochemical study. J Pathol 1995;176:183–190.
18.
Takeuchi M, Otsuka T, Matsui N, et al: Aberrant production of gliostatin/platelet-derived endothelial cell growth factor in rheumatoid synovium. Arthritis Rheum 1994;37:662–672.
19.
Kasugai K, Joh T, Kataoka H, et al: Evidence for participation of gliostatin/platelet-derived endothelial cell growth factor in gastric ulcer healing. Life Sci 1997;61:1899–1906.
20.
Creamer D, Jaggar R, Allen M, et al: Overexpression of the angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase in psoriatic epidermis. Br J Dermatol 1997;137:851–855.
21.
Okada K, Yokoyama K, Okihara K, et al: Immunohistochemical localization of platelet-derived endothelial cell growth factor expression and its relation to angiogenesis in prostate. Urology 2001;57:376–381.
22.
Suzuki K, Morita T, Hashimoto S, Tokue A: Thymidine phosphorylase/platelet-derived endothelial cell growth factor (PD-ECGF) associated with prognosis in renal cell carcinoma. Urol Res 2001;29:7–12.
23.
Konda R, Sato H, Sakai K, et al: Expression of platelet-derived endothelial cell growth factor and its potential role in up-regulation of angiogenesis in scarred kidneys secondary to urinary tract diseases. Am J Pathol 1999;155:1587–1597.
24.
Goto H, Kohno K, Sone S, et al: Interferon-dependent induction of thymidine phosphorylase/platelet-derived endothelial growth factor through activated sequence-like element in human macrophages. Cancer Res 2001;61:469–473.
25.
Ishii R, Takiguchi N, Oda K, et al: Thymidine phosphorylase expression is useful in selecting adjuvant chemotherapy for stage III gastric cancer. Int J Oncol 2001;19:717–722.
26.
Choi YJ, Chakraborty S, Nguyen V, et al: Peritubular capillary loss is associated with chronic tubulointerstitial injury in human kidney: altered expression of vascular endothelial growth factor. Hum Pathol 2000;31:1491–1497.
27.
Folkman J, Cortran R: Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol 1976;16:207–248.
28.
Polverini PJ, Cotran PS, Gimbrone MA Jr, Unanue ER: Activated macrophages induce vascular proliferation. Nature 1977;269:804–806.
29.
Majno G: Chronic inflammation: links with angiogenesis and wound healing. Am J Pathol 1998;153:1035–1039.
30.
Ooi BS, MacCarthy EP, Hsu A, Ooi YM: Human mononuclear cell modulation of endothelial cell proliferation. J Lab Clin Med 1983;102:428–433.
31.
Polverini PJ, Leibovich SJ: Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages. Lab Invest 1984;51:635–642.
32.
Eda H, Fujimoto K, Watanabe S, et al: Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′-deoxy-5-fluorouridine. Cancer Chemother Pharmacol 1993;32:333–338.
33.
Duk-Hee Kang, Richard J: Johnson: Vascular endothelial growth factor: A new player in the pathogenesis of renal fibrosis. Curr Opin Nephrol Hypertens 2003;12:43–49.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.