Skip to main content

Advertisement

SpringerLink
Log in

Renal progenitors and childhood: from development to disorders

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Nephropathies arise from conditions that alter nephron development or trigger nephron damage during neonatal, juvenile, and adult stages of life. Much evidence suggests that a key role in maintaining kidney integrity, homeostasis, and regenerative capacity is played by a population of progenitor cells resident in the organ. Although the primary goals in the field of renal progenitor cells are understanding their ability to regenerate nephrons and to restore damaged kidney function, the discovery of these cells could also be used to elucidate the molecular and pathophysiological basis of kidney diseases. As a result, once the identification of a subset of progenitor cells capable of kidney regeneration has been obtained, the increasing knowledge about their characteristics and about the mechanisms of renal development had pointed out the possibility of understanding the molecular basis of kidney diseases, so that, nowadays, some renal disorders could also be related to renal progenitor dysfunction. In this review, we summarize the evidence on the existence of renal progenitors in fetal and adult kidneys and discuss their role in physiology as well as in the pathogenesis of renal disorders with a particular focus on childhood age.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Romagnani P (2010) From Proteus to Prometeus: learning from fish to modulate regeneration. J Am Soc Nephrol 21:726–728

    Article  CAS  PubMed  Google Scholar 

  2. Shahragim T (2009) Stem cell: what’s in the name? Nat Rep Stem Cells. doi:10.1038/stemcells.2009.90

    Google Scholar 

  3. Romagnani P, Lasagni L, Remuzzi G (2013) Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Nat Rev Nephrol 9(3):137–146

    Article  CAS  PubMed  Google Scholar 

  4. Mc Campbell KK, Wingert RA (2012) Renal stem cells: fact or science fiction? Biochem J 444:153–168

    Article  CAS  Google Scholar 

  5. Dressler GR (2006) The cellular basis of kidney development. Annu Rev Cell Dev Biol 22:509–529

    Article  CAS  PubMed  Google Scholar 

  6. Schedl A (2007) Renal abnormalities and their developmental origin. Nat Rev Genet 8:791–802

    Article  CAS  PubMed  Google Scholar 

  7. Kobayashi A, Valerius MT, Mugford JW, Carroll TJ, Self M, Oliver G, McMahon AP (2008) Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development. Cell Stem Cell 3(2):169–181

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Barker N, Rookmaaker MB, Kujala P, Ng A, Leushacke M, Snippert H, van de Wetering M, Tan S, Van Es JH, Huch M, Poulsom R, Verhaar MC, Peters PJ, Clevers H (2012) Lgr5(+ve) stem/progenitor cells contribute to nephron formation during kidney development. Cell Rep 2(3):540–552

    Article  CAS  PubMed  Google Scholar 

  9. Bhat PV, Manolescu DC (2008) Role of vitamin A in determining nephron mass and possible relationship to hypertension. J Nutr 138(8):1407–1410

    CAS  PubMed  Google Scholar 

  10. Bertram JF, Douglas-Denton RN, Diouf B, Hughson MD, Hoy WE (2011) Human nephron number: implications for health and disease. Pediatr Nephrol 26:1529–1533

    Article  PubMed  Google Scholar 

  11. Lazzeri E, Crescioli C, Ronconi E, Mazzinghi B, Sagrinati C, Netti GS, Angelotti ML, Parente E, Ballerini L, Cosmi L, Maggi L, Gesualdo L, Rotondi M, Annunziato F, Maggi E, Lasagni L, Serio M, Romagnani S, Vannelli GB, Romagnani P (2007) Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. J Am Soc Nephrol 18(12):3128–3138

    Article  CAS  PubMed  Google Scholar 

  12. 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 (2006) Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys. J Am Soc Nephrol 17(9):2443–2456

    Article  CAS  PubMed  Google Scholar 

  13. 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 (2009) Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol 20(2):322–332

    Article  CAS  PubMed  Google Scholar 

  14. Appel D, Kershaw DB, Smeets B, Yuan G, Fuss A, Frye B, Elger M, Kriz W, Floege J, Moeller MJ (2009) Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol 20(2):333–343

    Article  CAS  PubMed  Google Scholar 

  15. Angelotti ML, Ronconi E, Ballerini L, Peired A, Mazzinghi B, Sagrinati C, Parente E, Gacci M, Carini M, Rotondi M, Fogo AB, Lazzeri E, Lasagni L, Romagnani P (2012) Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury. Stem Cells 30(8):1714–1725

    Article  CAS  PubMed  Google Scholar 

  16. Romagnani P (2009) Toward the identification of a “renopoietic system”? Stem Cells 27(9):2247–2253

    Article  PubMed Central  PubMed  Google Scholar 

  17. Mazzinghi B, Ronconi E, Lazzeri E, Sagrinati C, Ballerini L, Angelotti ML, Parente E, Mancina R, Netti GS, Becherucci F, Gacci M, Carini M, Gesualdo L, Rotondi M, Maggi E, Lasagni L, Serio M, Romagnani S, Romagnani P (2008) Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med 205(2):479–490

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Sanna-Cherchi S, Caridi G, Weng PL, Scolari F, Perfumo F, Gharavi AG, Ghiggeri GM (2007) Genetic approaches to human renal agenesis/hypoplasia and dysplasia. Pediatr Nephrol 22(10):1675–1684

    Article  PubMed Central  PubMed  Google Scholar 

  19. Davies JA, Fisher CE (2002) Genes and proteins in renal development. Exp Nephrol 10:102–113

    Article  CAS  PubMed  Google Scholar 

  20. Zhang Z, Iglesias D, Eliopoulos N, El Kares R, Chu L, Romagnani P, Goodyer P (2011) A variant OSR1 allele which disturbs OSR1 mRNA expression in renal progenitor cells is associated with reduction of newborn kidney size and function. Hum Mol Genet 20(21):4167–4174

    Article  CAS  PubMed  Google Scholar 

  21. McCarroll MN, Lewis ZR, Culbertson MD, Martin BL, Kimelman D, Nechiporuk AV (2012) Graded levels of Pax2a and Pax8 regulate cell differentiation during sensory placode formation. Development 139(15):2740–2750

    Article  CAS  PubMed  Google Scholar 

  22. Kochhar A, Fischer SM, Kimberling WJ, Smith RJ (2007) Branchio-oto-renal syndrome. Am J Med Genet A 143A(14):1671–1678

    Article  CAS  PubMed  Google Scholar 

  23. Aboudehen K, Hilliard S, Saifudeen Z, El-Dahr SS (2012) Mechanisms of p53 activation and physiological relevance in the developing kidney. Am J Physiol Renal Physiol 302(8):F928–F940

    Article  CAS  PubMed  Google Scholar 

  24. Ahn SY, Kim Y, Kim ST, Swat W, Miner JH (2013) Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor population during kidney development. J Am Soc Nephrol 24:1127–1138

    Article  CAS  PubMed  Google Scholar 

  25. Park JS, Valerius MT, McMahon AP (2007) Wnt/beta-catenin signaling regulates nephron induction during mouse kidney development. Development 134:2533–2539

    Article  CAS  PubMed  Google Scholar 

  26. Grouls S, Iglesias DM, Wentzensen N, Moeller MJ, Bouchard M, Kemler R, Goodyer P, Niggli F, Gröne HJ, Kriz W, Koesters R (2012) Lineage specification of parietal epithelial cells requires β-catenin/Wnt signaling. J Am Soc Nephrol 23(1):63–72

    Article  CAS  PubMed  Google Scholar 

  27. Wang Q, Lan Y, Cho ES, Maltby KM, Jiang R (2005) Odd-skipped related 1 (Odd 1) is an essential regulator of heart and urogenital. Dev Biol 288:582–594

    Article  CAS  PubMed  Google Scholar 

  28. Chai OH, Song CH, Park SK, Kim W, Cho ES (2013) Molecular regulation of kidney development. Anat Cell Biol 46(1):19–31

    Article  PubMed Central  PubMed  Google Scholar 

  29. Black MJ, Sutherland MR, Gubhaju L, Kent AL, Dahlstrom JE, Moore L (2013) When birth comes early: effects on nephrogenesis. Nephrology 18(3):180–182

    Article  PubMed  Google Scholar 

  30. Schreuder MF (2012) Safety in glomerular numbers. Pediatr Nephrol 27(10):1881–1887

    Article  PubMed Central  PubMed  Google Scholar 

  31. Makrakis J, Zimanyi MA, Black MJ (2007) Retinoic acid enhances nephron endowment in rats exposed to maternal protein restriction. Pediatr Nephrol 22:1861–1867

    Article  PubMed  Google Scholar 

  32. Lelièvre-Pégorier M, Vilar J, Ferrier ML, Moreau E, Freund N, Gilbert T, Merlet-Bénichou C (1998) Mild vitamin A deficiency leads to inborn nephron deficit in the rat. Kidney Int 54(5):1455–1462

    Article  PubMed  Google Scholar 

  33. Batourina E, Gim S, Bello N, Shy M, Clagett-Dame M, Srinivas S, Costantini F, Mendelsohn C (2001) Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Nat Genet 27(1):74–78

    Article  CAS  PubMed  Google Scholar 

  34. Wingert RA, Selleck R, Yu J, Song HD, Chen Z, Song A, Zhou Y, Thisse B, Thisse C, McMahon AP, Davidson AJ (2007) The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros. PLoS Genet 3(10):1922–1938

    Article  CAS  PubMed  Google Scholar 

  35. Vaughan MR, Pippin JW, Griffin SV, Krofft R, Fleet M, Haseley L, Shankland SJ (2005) ATRA induces podocyte differentiation and alters nephrin and podocin expression in vitro and in vivo. Kidney Int 68(1):133–144

    Article  CAS  PubMed  Google Scholar 

  36. Zhang J, Pippin JW, Vaughan MR, Krofft RD, Taniguchi Y, Romagnani P, Nelson PJ, Liu ZH, Shankland SJ (2012) Retinoids augment the expression of podocyte proteins by glomerular parietal epithelial cells in experimental glomerular disease. Nephron Exp Nephrol 121(1–2):e23–e37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Walkley CR, Olsen GH, Dworkin S, Fabb SA, Swann J, McArthur GA, Westmoreland SV, Chambon P, Scadden DT, Purton LE (2007) A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell 129(6):1097–1110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Young NS, Maciejewski J (1997) The pathophysiology of acquired aplastic anemia. N Engl J Med 336(19):1365–1372

    Article  CAS  PubMed  Google Scholar 

  39. Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C, Mazzinghi B, Ronconi E, Becherucci F, Benigni A, Steenbergen E, Lasagni L, Remuzzi G, Wetzels J, Romagnani P (2009) Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol 20(12):2593–2603

    Article  PubMed  Google Scholar 

  40. Smeets B, Uhlig S, Fuss A, Mooren F, Wetzels JF, Floege J, Moeller MJ (2009) Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells. J Am Soc Nephrol 20(12):2604–2615

    Article  PubMed  Google Scholar 

  41. Ryu M, Migliorini A, Miosge N, Gross O, Shankland S, Brinkkoetter PT, Hagmann H, Romagnani P, Liapis H, Anders HJ (2012) Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury. J Pathol. doi:10.1002/path.4046

    Google Scholar 

  42. Sicking EM, Fuss A, Uhlig S, Jirak P, Dijkman H, Wetzels J, Engel DR, Urzynicok T, Heidenreich S, Kriz W, Kurts C, Ostendorf T, Floege J, Smeets B, Moeller MJ (2012) Subtotal ablation of parietal epithelial cells induces crescent formation. J Am Soc Nephrol 23(4):629–640

    Article  CAS  PubMed  Google Scholar 

  43. Smeets B, Kuppe C, Sicking EM, Fuss A, Jirak P, van Kuppevelt TH, Endlich K, Wetzels JF, Gröne HJ, Floege J, Moeller MJ (2011) Parietal epithelial cells participate in the formation of sclerotic lesions in focal segmental glomerulosclerosis. J Am Soc Nephrol 22(7):1262–1274

    Article  CAS  PubMed  Google Scholar 

  44. Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB, Wiggins RC (2005) Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 16(10):2941–2952

    Article  CAS  PubMed  Google Scholar 

  45. Peti-Peterdi J, Sipos A (2010) A high-powered view of the filtration barrier. J Am Soc Nephrol 21:1835–1841

    Article  PubMed  Google Scholar 

  46. Shankland SJ, Anders HJ, Romagnani P (2013) Glomerular parietal epithelial cells in kidney physiology, pathology, and repair. Curr Opin Nephrol Hypertens. doi:10.1097/MNH.0b013e32835fefd4

    PubMed  Google Scholar 

  47. 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 (2010) Notch activation differentially regulates renal progenitors proliferation and differentiation toward the podocyte lineage in glomerular disorders. Stem Cells 28(9):1674–1685

    Article  PubMed Central  PubMed  Google Scholar 

  48. Lasagni L, Lazzeri E, Shankland SJ, Anders HJ, Romagnani P (2013) Podocyte mitosis—a catastrophe. Curr Mol Med 13(1):13–23

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Darisipudi MN, Kulkarni OP, Sayyed SG, Ryu M, Migliorini A, Sagrinati C, Parente E, Vater A, Eulberg D, Klussmann S, Romagnani P, Anders HJ (2011) Dual blockade of the homeostatic Chemokine CXCL12 and the proinflammatory Chemokine CCL2 has additive protective effects on diabetic kidney disease. Am J Pathol 179(1):116–124

    Article  CAS  PubMed  Google Scholar 

  50. Ohtaka A, Ootaka T, Sato H, Soma J, Sato T, Saito T, Ito S (2002) Significance of early phenotypic change of glomerular podocytes detected by Pax2 in primary focal segmental glomerulosclerosis. Am J Kidney Dis 39(3):475–485

    Article  PubMed  Google Scholar 

  51. Fatima H, Moeller MJ, Smeets B, Yang HC, D’Agati VD, Alpers CE, Fogo AB (2012) Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant. Clin J Am Soc Nephrol 7(11):1852–1858

    Article  PubMed  Google Scholar 

  52. Hodgin JB, Borczuk AC, Nasr SH, Markowitz GS, Nair V, Martini S, Eichinger F, Vining C, Berthier CC, Kretzler M, D’Agati VD (2010) A molecular profile of focal segmental glomerulosclerosis from formalin-fixed, paraffin-embedded tissue. Am J Pathol 177(4):1674–1686

    Article  CAS  PubMed  Google Scholar 

  53. 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, Huber TB, Liapis H, Lazzeri E, Lasagni L, Romagnani P (2013) Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J Am Soc Nephrol 24(11):1756–1768

    Google Scholar 

  54. Pode-Shakked N, Dekel B (2011) Wilms tumor–a renal stem cell malignancy? Pediatr Nephrol 26(9):1535–1543

    Article  PubMed  Google Scholar 

  55. Pode-Shakked N, Shukrun R, Mark-Danieli M, Tsvetkov P, Bahar S, Pri-Chen S, Goldstein RS, Rom-Gross E, Mor Y, Fridman E, Meir K, Simon A, Magister M, Kaminski N, Goldmacher VS, Harari-Steinberg O, Dekel B (2013) The isolation and characterization of renal cancer initiating cells from human Wilms tumour xenografts unveils new therapeutic targets. EMBO Mol Med 5(1):18–37

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Lindgren D, Boström AK, Nilsson K, Hansson J, Sjölund J, Möller C, Jirström K, Nilsson E, Landberg G, Axelson H, Johansson ME (2011) Isolation and characterization of progenitor-like cells from human renal proximal tubules. Am J Pathol 178(2):828–837

    Article  PubMed  Google Scholar 

  57. Romagnani P (2011) Family portrait: renal progenitor of Bowman’s capsule and its tubular brothers. Am J Pathol 178(2):490–493

    Article  PubMed  Google Scholar 

  58. Romagnani P (2013) Of mice and men: the riddle of tubular regeneration. J Pathol 229:641–644

    Article  PubMed  Google Scholar 

  59. Smeets B, Boor P, Dijkman H, Sharma SV, Jirak P, Mooren F, Berger K, Bornemann J, Gelman IH, Floege J, van der Vlag J, Wetzels JF, Moeller MJ (2013) Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration. J Pathol 229(5):645–659

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Nephrology and Dialysis Unit, Meyer Children’s University Hospital, Florence, Italy

    Francesca Becherucci & Paola Romagnani

  2. Excellence Centre for Research, Transfer and High Education for the development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy

    Francesca Becherucci, Elena Lazzeri, Laura Lasagni & Paola Romagnani

  3. Department of Clinical and Experimental Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Paola Romagnani

Authors
  1. Francesca Becherucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Lazzeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Lasagni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paola Romagnani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Romagnani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Becherucci, F., Lazzeri, E., Lasagni, L. et al. Renal progenitors and childhood: from development to disorders. Pediatr Nephrol 29, 711–719 (2014). https://doi.org/10.1007/s00467-013-2686-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-013-2686-2

Keywords

Search

Navigation