Background/Aims: We previously reported that increase in plasma homocysteine (Hcys) levels by a 6-week methionine treatment produced remarkable glomerular injury. However, the mechanism by which hyperhomocysteinemia (hHcys) produces glomerular injury remains unknown. The present study was to observe when glomerular injury happens during hHcys and to explore the possible role of podocyte injury in the progression of glomerulosclerosis associated with hHcys. Methods: Uninephrectomized Sprague-Dawley rats treated with methionine were used to examine the time course of glomerular injury induced by hHcys. Results: Creatinine clearance was not different until rats were treated with methionine for 6 weeks, although plasma Hcys levels significantly increased at the 1st week of methionine treatment. However, urinary albumin excretion increased at the 2nd week of methionine treatment. Morphological examinations showed that mesangial expansion occurred at the 2nd week and podocyte effacement was also observed as processed glomerular damage during hHcys. Immunofluorescence analyses demonstrated that podocin and nephrin expressions were reduced, while α-actinin-4 increased during hHcys. Conclusions: Increased plasma Hcys level is an important pathogenic factor resulting in glomerular injury even in the very early time of hHcys. These pathogenic effects of Hcys are associated with podocyte injury and changed expression and distribution of podocyte-associated proteins.

Dennis VW, Nurko S, Robinson K: Hyperhomocysteinemia: detection, risk assessment, and treatment. Curr Opin Nephrol Hypertens 1997;6:483–488.
Dennis VW, Robinson K: Homocysteinemia and vascular disease in end-stage renal disease. Kidney Int Suppl 1996;57:S11–S17.
Ducloux D, Motte G, Challier B, Gibey R, Chalopin JM: Serum total homocysteine and cardiovascular disease occurrence in chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000;11:134–137.
Li N, Chen YF, Zou AP: Implications of hyperhomocysteinemia in glomerular sclerosis in hypertension. Hypertension 2002;39:443–448.
Tyagi N, Moshal KS, Lominadze D, Ovechkin AV, Tyagi SC: Homocysteine-dependent cardiac remodeling and endothelial-myocyte coupling in a 2 kidney, 1 clip Goldblatt hypertension mouse model. Can J Physiol Pharmacol 2005;83:583–594.
Yi F, Zhang AY, Li N, Muh RW, Fillet M, Renert AF, Li PL: Inhibition of ceramide-redox signaling pathway blocks glomerular injury in hyperhomocysteinemic Rats. Kidney Int 2006;70:88–96.
Yi F, Zhang AY, Janscha JL, Li PL, Zou AP: Homocysteine activates NADH/NADPH oxidase through ceramide-stimulated Rac activity in rat mesangial cells. Kidney Int 2004;66:1977–1987.
Smoyer WE, Mundel P: Regulation of podocyte structure during the development of nephrotic syndrome. J Mol Med 1998;76:172–183.
Shirato I: Podocyte process effacement in vivo. Microsc Res Tech 2002;57:241–246.
Barri YM, Munshi NC, Sukumalchantra S, Abulezz SR, Bonsib SM, Wallach J, Walker PD: Podocyte injury associated glomerulopathies induced by pamidronate. Kidney Int 2004;65:634–641.
Durvasula RV, Shankland SJ: Podocyte injury and targeting therapy: an update. Curr Opin Nephrol Hypertens 2006;15:1–7.
Chen YF, Li PL, Zou AP: Effect of hyperhomocysteinemia on plasma or tissue adenosine levels and renal function. Circulation 2002;106:1275–1281.
Saran AM, Yuan H, Takeuchi E, McLaughlin M, Salant DJ: Complement mediates nephrin redistribution and actin dissociation in experimental membranous nephropathy. Kidney Int 2003;64:2072–2078.
Ingram AJ, Krepinsky JC, James L, Austin RC, Tang D, Salapatek AM, Thai K, Scholey JW: Activation of mesangial cell MAPK in response to homocysteine. Kidney Int 2004;66:733–745.
Mundel P, Kriz W: Structure and function of podocytes: an update. Anat Embryol 1995;192:385–397.
Laurens W, Battaglia C, Foglieni C, De Vos R, Malanchini B, Van Damme B, Vanrenterghem Y, Remuzzi G, Remuzzi A: Direct podocyte damage in the single nephron leads to albuminuria in vivo. Kidney Int 1995;47:1078–1086.
Messina A, Davies DJ, Dillane PC, Ryan GB: Glomerular epithelial abnormalities associated with the onset of proteinuria in aminonucleoside nephrosis. Am J Pathol 1987;126:220–229.
Shankland SJ: The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 2006;69:2131–2147.
Mundel P, Shankland SJ: Podocyte biology and response to injury. J Am Soc Nephrol 2002;13:3005–3015.
Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K: Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Mol Cell 1998;1:575–582.
Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephritic syndrome. Nat Genet 2000;24:349–354.
Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS: Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 1999;286:312–315.
Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR: Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 2000;24:251–256.
Lehtonen S, Ryan JJ, Kudlicka K, Iino N, Zhou H, Farquhar MG: Cell junction-associated proteins IQGAP1, MAGI-2, CASK, spectrins, and alpha-actinin are components of the nephrin multiprotein complex. Proc Natl Acad Sci USA 2005;102:9814–9819.
Koop K, Eikmans M, Baelde HJ, Kawachi H, De Heer E, Paul LC, Bruijn JA: Expression of podocyte-associated molecules in acquired human kidney diseases. J Am Soc Nephrol 2003;14:2063–2071.
Luimula P, Sandstrom N, Novikov D, Holthofer H: Podocyte-associated molecules in puromycin aminonucleoside nephrosis of the rat. Lab Invest 2002;82:713–718.
Whiteside CI, Cameron R, Munk S, Levy J: Podocytic cytoskeletal disaggregation and basement-membrane detachment in puromycin aminonucleoside nephrosis. Am J Pathol 1993;142:1641–1653.
Otey CA, Vasquez GB, Burridge K, Erickson BW: Mapping of the alpha-actinin binding site within the beta 1 integrin cytoplasmic domain. J Biol Chem 1993;268:21193–21197.
Smoyer WE, Mondel P, Gupta A, Welsh MJ: Podocyte alpha-actinin induction precedes foot process effacement in experimental nephrotic syndrome. Am J Physiol 1997;273:F150–F157.
Greiber S, Munzel T, Kastner S, Muller B, Schollmeyer P, Pavenstadt H: NAD(P)H oxidase activity in cultured human podocytes: effects of adenosine triphosphate. Kidney Int 1998;53:654–663.
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.