Abstract
The glomerulus is a complex physiological structure that, as well as maintaining a selective filtration barrier, participates in the control of renal blood flow and blood pressure. Recently there has been a surge of interest in the podocyte, as the main player in this functional unit, driven by key discoveries of genes mutated in hereditary conditions, that result in breakdown of barrier functions. This has been accompanied by the development of powerful new molecular, cellular and animal tools to enable study at a level of detail not previously possible. How this emerging information is shaping our understanding of glomerular biology, and ultimately our understanding of the pathophysiology of glomerular diseases, is outlined here.
Journal Section:
Minireview
References
1.
Saxen L, Lehtonen E: Embryonic kidney in organ culture. Differentiation 1987;36:2–11.
[PubMed]
2.
Schedl A, Hastie ND: Cross-talk in kidney development. Curr Opin Genet Dev 2000;10:543–549.
[PubMed]
3.
Scharnhorst V, van der Eb AJ, Jochemsen AG: WT1 proteins: Functions in growth and differentiation. Gene 2001;273:141–161.
[PubMed]
4.
Ryan GB, Rodewald R, Karnovsky MJ: An ultrastructural study of the glomerular slit diaphragm in aminonucleoside nephrosis. Lab Invest 1975;33:461–468.
[PubMed]
5.
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.
[PubMed]
6.
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 nephrotic syndrome. Nat Genet 2000;24:349–354.
[PubMed]
7.
Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P: Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 2001;108:1621–1629.
[PubMed]
8.
Huber TB, Hartleben B, Kim J, Schmidts M, Schermer B, Keil A, Egger L, Lecha RL, Borner C, Pavenstadt H, Shaw AS, Walz G, Benzing T: Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol 2003;23:4917–4928.
[PubMed]
9.
Lahdenpera J, Kilpelainen P, Liu XL, Pikkarainen T, Reponen P, Ruotsalainen V, Tryggvason K: Clustering-induced tyrosine phosphorylation of nephrin by Src family kinases. Kidney Int 2003;64:404–413.
[PubMed]
10.
Huber TB, Kottgen M, Schilling B, Walz G, Benzing T: Interaction with podocin facilitates nephrin signaling. J Biol Chem 2001;276:41543–41546.
[PubMed]
11.
Koziell A, Grech V, Hussain S, Lee G, Lenkkeri U, Tryggvason K, Scambler P: Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet 2002;11:379–388.
12.
Inoue T, Yaoita E, Kurihara H, Shimizu F, Sakai T, Kobayashi T, Ohshiro K, Kawachi H, Okada H, Suzuki H, Kihara I, Yamamoto T: FAT is a component of glomerular slit diaphragms. Kidney Int 2001;59:1003–1012.
[PubMed]
13.
Donoviel DB, Freed DD, Vogel H, Potter DG, Hawkins E, Barrish JP, Mathur BN, Turner CA, Geske R, Montgomery CA, Starbuck M, Brandt M, Gupta A, Ramirez-Solis R, Zambrowicz BP, Powell DR: Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Mol Cell Biol 2001;21:4829–4836.
[PubMed]
14.
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.
[PubMed]
15.
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.
[PubMed]
16.
Saleem MA, Ni L, Witherden I, Tryggvason K, Ruotsalainen V, Mundel P, Mathieson PW: Co-localization of nephrin, podocin and the actin cytoskeleton: Evidence for a role in podocyte foot process formation. Am J Pathol 2002;161:1459–1466.
[PubMed]
17.
Miner JH: Renal basement membrane components. Kidney Int 1999;56:2016–2024.
[PubMed]
18.
Kretzler M, Teixeira VP, Unschuld PG, Cohen CD, Wanke R, Edenhofer I, Mundel P, Schlondorff D, Holthofer H: Integrin-linked kinase as a candidate downstream effector in proteinuria. Faseb J 2001;15:1843–1845.
[PubMed]
19.
Nagata M, Nakayama K, Terada Y, Hoshi S, Watanabe T: Cell cycle regulation and differentiation in the human podocyte lineage. Am J Pathol 1998;153:1511–1520.
[PubMed]
20.
Barisoni L, Mokrzycki M, Sablay L, Nagata M, Yamase H, Mundel P: Podocyte cell cycle regulation and proliferation in collapsing glomerulopathies. Kidney Int 2000;58:137–143.
[PubMed]
21.
Kriz W: Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc Res Tech 2002;57:189–195.
[PubMed]
22.
Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE: Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111:707–716.
[PubMed]
23.
Satchell SC, Harper SJ, Tooke JE, Kerjaschki D, Saleem MA, Mathieson PW: Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor. J Am Soc Nephrol 2002;13:544–550.
[PubMed]
24.
Eremina V, Wong MA, Cui S, Schwartz L, Quaggin SE: Glomerular-specific gene excision in vivo. J Am Soc Nephrol 2002;13:788–793.
[PubMed]
25.
Saleem MA, O’Hare MJ, Reiser J, Coward RJ, Inward CD, Farren T, Xing CY, Ni L, Mathieson PW, Mundel P: A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol 2002;13:630–638.
[PubMed]
© 2003 S. Karger AG, Basel
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.
2004
You do not currently have access to this content.
