Abstract
Background: For many years, the glomerulus was considered incapable of regeneration. However, experimental and clinical evidence challenged this concept and showed that glomerular injury and even glomerulosclerosis can undergo regression under certain circumstances. The problem with glomerular regeneration is centered around the podocyte, a highly specialized cell that is the critical constituent of the glomerular filtration barrier. Summary: Podocytes are characterized by a complex cytoskeleton that makes them unable to proliferate. Thus, once their depletion reaches a specific threshold, it is considered to be irreversible. The discovery of cells with the aptitude to differentiate into podocytes in the adult kidney, i.e. renal progenitor cells (RPCs), was a critical step in understanding the mechanisms of glomerular repair. Accumulating evidence suggests that a tight regulation of many different signaling pathways, such as Notch, Wnt, and microRNA, is involved in a correct regenerative process and that an altered regulation of these same signaling pathways in RPCs triggers the generation of focal segmental glomerulosclerosis lesions. In particular, regeneration is severely impaired by proteinuria, when albumin sequesters retinoic acid and blocks RPC differentiation in podocytes. Key Messages: RPC maintenance and differentiating potential are regulated by complex mechanisms that can be implemented following glomerular injury and can be manipulated to activate regeneration for therapeutic purposes. A better understanding of the phenomenon of glomerular regeneration paves the way for the prevention and treatment of glomerular diseases.
References
1.
Lasagni L, Lazzeri E, Shankland SJ, Anders HJ, Romagnani P: Podocyte mitosis - a catastrophe. Curr Mol Med 2013;13:13-23.
[PubMed]
2.
Wiggins RC: The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int 2007;71:1205-1214.
[PubMed]
3.
Wanner N, Hartleben B, Herbach N, Goedel M, Stickel N, Zeiser R, Walz G, Moeller M, Grahammer F, Huber TB: Unraveling the role of podocyte turnover in glomerular aging and injury. J Am Soc Nephrol 2014, E-pub ahead of print.
[PubMed]
4.
Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006;116:288-296.
[PubMed]
5.
Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M: Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998;339:69-75.
[PubMed]
6.
Poulsom R, Forbes SJ, Hodivala-Dilke K, Ryan E, Wyles S, Navaratnarasah S, Jeffery R, Hunt T, Alison M, Cook T, Pusey C, Wright NA: Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol 2001;195:229-235.
[PubMed]
7.
Sagrinati C, Ronconi E, Lazzeri E, Lasagni L, Romagnani P: Stem-cell approaches for kidney repair: choosing the right cells. Trends Mol Med 2008;14:277-285.
[PubMed]
8.
Zoja C, Garcia PB, Rota C, Conti S, Gagliardini E, Corna D, Zanchi C, Bigini P, Benigni A, Remuzzi G, Morigi M: Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in Adriamycin-induced nephropathy. Am J Physiol Renal Physiol 2012;303:F1370-F1381.
[PubMed]
9.
Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F, Ronconi E, Meini C, Gacci M, Squecco R, Carini M, Gesualdo L, Francini F, Maggi E, Annunziato F, Lasagni L, Serio M, Romagnani S, Romagnani P: Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. J Am Soc Nephrol 2006;17:2443-2456.
[PubMed]
10.
Ronconi E, Sagrinati C, Angelotti ML, Lazzeri E, Mazzinghi B, Ballerini L, Parente E, Becherucci F, Gacci M, Carini M, Maggi E, Serio M, Vannelli GB, Lasagni L, Romagnani S, Romagnani P: Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol 2009;20:322-332.
[PubMed]
11.
Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ: Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 2009;20:333-343.
[PubMed]
12.
Pippin JW, Sparks MA, Glenn ST, Buitrago S, Coffman TM, Duffield JS, Gross KW, Shankland SJ: Cells of renin lineage are progenitors of podocytes and parietal epithelial cells in experimental glomerular disease. Am J Pathol 2013;183:542-557.
[PubMed]
13.
Grahammer F, Wanner N, Huber T: Podocyte regeneration: who can become a podocyte? Am J Pathol 2013;183:333-335.
[PubMed]
14.
Koch U, Lehal R, Radtke F: Stem cells living with a Notch. Development 2013;140:689-704.
[PubMed]
15.
Lasagni L, Ballerini L, Angelotti ML, Parente E, Sagrinati C, Mazzinghi B, Peired A, Ronconi E, Becherucci F, Bani D, Gacci M, Carini M, Lazzeri E, Romagnani P: Notch activation differentially regulates renal progenitors proliferation and differentiation toward the podocyte lineage in glomerular disorders. Stem Cells 2010;28:1674-1685.
[PubMed]
16.
Ueno T, Kobayashi N, Nakayama M, Takashima Y, Ohse T, Pastan I, Pippin JW, Shankland SJ, Uesugi N, Matsusaka T, Nagata M: Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss. Kidney Int 2013;83:1065-1075.
[PubMed]
17.
Grouls S, Iglesias DM, Wentzensen N, Moeller MJ, Bouchard M, Kemler R, Goodyer P, Niggli F, Gröne HJ, Kriz W, Koesters R: Lineage specification of parietal epithelial cells requires β-catenin/Wnt signaling. J Am Soc Nephrol 2012;23:63-72.
[PubMed]
18.
Zhang J, Pippin JW, Vaughan MR, Krofft RD, Taniguchi Y, Romagnani P, Nelson PJ, Liu ZH, Shankland SJ: Retinoids augment the expression of podocyte proteins by glomerular parietal epithelial cells in experimental glomerular disease. Nephron Exp Nephrol 2012;121:e23-e37.
[PubMed]
19.
Sallustio F, Serino G, Costantino V, Curci C, Cox SN, De Palma G, Schena FP: miR-1915 and miR-1225-5p regulate the expression of CD133, PAX2 and TLR2 in adult renal progenitor cells. PLoS One 2013;8:e68296.
[PubMed]
20.
Wu J, Zheng C, Fan Y, Zeng C, Chen Z, Qin W, Zhang C, Zhang W, Wang X, Zhu X, Zhang M, Zen K, Liu Z: Downregulation of microRNA-30 facilitates podocyte injury and is prevented by glucocorticoids. J Am Soc Nephrol 2014;25:92-104.
[PubMed]
21.
Gebeshuber CA, Kornauth C, Dong L, Sierig R, Seibler J, Reiss M, Tauber S, Bilban M, Wang S, Kain R, Böhmig GA, Moeller MJ, Gröne HJ, Englert C, Martinez J, Kerjaschki D: Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1. Nat Med 2013;19:481-487.
[PubMed]
22.
Niranjan T, Bielesz B, Gruenwald A, Ponda MP, Kopp JB, Thomas DB, Susztak K: The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 2008;14:290-298.
[PubMed]
23.
Kato H, Gruenwald A, Suh JH, Miner JH, Barisoni-Thomas L, Taketo MM, Faul C, Millar SE, Holzman LB, Susztak K: Wnt/β-catenin pathway in podocytes integrates cell adhesion, differentiation, and survival. J Biol Chem 2011;286:26003-26015.
[PubMed]
24.
Rizzo P, Perico N, Gagliardini E, Novelli R, Alison MR, Remuzzi G, Benigni A: Nature and mediators of parietal epithelial cell activation in glomerulonephritides of human and rat. Am J Pathol 2013;183:1769-1778.
[PubMed]
25.
Peired A, Angelotti ML, Ronconi E, la Marca G, Mazzinghi B, Sisti A, Lombardi D, Giocaliere E, Della Bona M, Villanelli F, Parente E, Ballerini L, Sagrinati C, Wanner N, Hubber TB, Liapis H, Lazzeri E, Lasagni L, Romagnani P: Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J Am Soc Nephrol 2013;24:1756-1768.
[PubMed]
© 2014 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.
2014
You do not currently have access to this content.
