Skip to main content

Advertisement

SpringerLink
Log in

Integrins in renal development

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

Abstract

The kidney develops from direct interactions between the ureteric bud and the metanephric mesenchyme. The ureteric bud gives rise to the collecting system and the metanephric mesenchyme to the nephrons. The complex process of renal development which occurs between these embryologically distinct structures is mediated by numerous factors, including the communication of cells with their surrounding extracellular matrix. Integrins are the principal cellular receptors for extracellular matrix proteins, and they play a role in organ and tissue development. In this review we focus on how integrins regulate renal development.

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

Similar content being viewed by others

References

  1. Costantini F, Kopan R (2010) Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev Cell 18:698–712

    Article  PubMed  CAS  Google Scholar 

  2. Reidy KJ, Rosenblum ND (2009) Cell and molecular biology of kidney development. Semin Nephrol 29:321–337

    Article  PubMed  CAS  Google Scholar 

  3. Khoshnoodi J, Pedchenko V, Hudson BG (2008) Mammalian collagen IV. Microsc Res Tech 71:357–370

    Article  PubMed  CAS  Google Scholar 

  4. Cosgrove D, Meehan DT, Grunkemeyer JA, Kornak JM, Sayers R, Hunter WJ, Samuelson GC (1996) Collagen COL4A3 knockout: a mouse model for autosomal Alport syndrome. Genes Dev 10:2981–2992

    Article  PubMed  CAS  Google Scholar 

  5. Miner JH, Sanes JR (1996) Molecular and functional defects in kidneys of mice lacking collagen alpha 3(IV): implications for Alport syndrome. J Cell Biol 135:1403–1413

    Article  PubMed  CAS  Google Scholar 

  6. Rheault MN, Kren SM, Thielen BK, Mesa HA, Crosson JT, Thomas W, Sado Y, Kashtan CE, Segal Y (2004) Mouse model of X-linked Alport syndrome. J Am Soc Nephrol 15:1466–1474

    Article  PubMed  Google Scholar 

  7. Miner JH, Li C (2000) Defective glomerulogenesis in the absence of laminin alpha5 demonstrates a developmental role for the kidney glomerular basement membrane. Dev Biol 217:278–289

    Article  PubMed  CAS  Google Scholar 

  8. Goldberg S, Adair-Kirk TL, Senior RM, Miner JH (2010) Maintenance of glomerular filtration barrier integrity requires laminin alpha5. J Am Soc Nephrol 21:579–586

    Article  PubMed  CAS  Google Scholar 

  9. Abrass CK, Berfield AK, Ryan MC, Carter WG, Hansen KM (2006) Abnormal development of glomerular endothelial and mesangial cells in mice with targeted disruption of the lama3 gene. Kidney Int 70:1062–1071

    Article  PubMed  CAS  Google Scholar 

  10. Noakes PG, Miner JH, Gautam M, Cunningham JM, Sanes JR, Merlie JP (1995) The renal glomerulus of mice lacking s-laminin/laminin beta 2: nephrosis despite molecular compensation by laminin beta 1. Nat Genet 10:400–406

    Article  PubMed  CAS  Google Scholar 

  11. Gawlik KI, Akerlund M, Carmignac V, Elamaa H, Durbeej M (2010) Distinct roles for laminin globular domains in laminin alpha1 chain mediated rescue of murine laminin alpha2 chain deficiency. PLoS ONE 5:e11549

    Article  PubMed  Google Scholar 

  12. Smyth N, Vatansever HS, Murray P, Meyer M, Frie C, Paulsson M, Edgar D (1999) Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J Cell Biol 144:151–160

    Article  PubMed  CAS  Google Scholar 

  13. Willem M, Miosge N, Halfter W, Smyth N, Jannetti I, Burghart E, Timpl R, Mayer U (2002) Specific ablation of the nidogen-binding site in the laminin gamma1 chain interferes with kidney and lung development. Development 129:2711–2722

    PubMed  CAS  Google Scholar 

  14. Miner JH, Yurchenco PD (2004) Laminin functions in tissue morphogenesis. Annu Rev Cell Dev Biol 20:255–284

    Article  PubMed  CAS  Google Scholar 

  15. Yurchenco PD, Patton BL (2009) Developmental and pathogenic mechanisms of basement membrane assembly. Curr Pharm Des 15:1277–1294

    Article  PubMed  CAS  Google Scholar 

  16. Murshed M, Smyth N, Miosge N, Karolat J, Krieg T, Paulsson M, Nischt R (2000) The absence of nidogen 1 does not affect murine basement membrane formation. Mol Cell Biol 20:7007–7012

    Article  PubMed  CAS  Google Scholar 

  17. Schymeinsky J, Nedbal S, Miosge N, Poschl E, Rao C, Beier DR, Skarnes WC, Timpl R, Bader BL (2002) Gene structure and functional analysis of the mouse nidogen-2 gene: nidogen-2 is not essential for basement membrane formation in mice. Mol Cell Biol 22:6820–6830

    Article  PubMed  CAS  Google Scholar 

  18. Bader BL, Smyth N, Nedbal S, Miosge N, Baranowsky A, Mokkapati S, Murshed M, Nischt R (2005) Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice. Mol Cell Biol 25:6846–6856

    Article  PubMed  CAS  Google Scholar 

  19. Rossi M, Morita H, Sormunen R, Airenne S, Kreivi M, Wang L, Fukai N, Olsen BR, Tryggvason K, Soininen R (2003) Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J 22:236–245

    Article  PubMed  CAS  Google Scholar 

  20. Arikawa-Hirasawa E, Watanabe H, Takami H, Hassell JR, Yamada Y (1999) Perlecan is essential for cartilage and cephalic development. Nat Genet 23:354–358

    Article  PubMed  CAS  Google Scholar 

  21. Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee KF (2001) Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410:1057–1064

    Article  PubMed  CAS  Google Scholar 

  22. Harvey SJ, Jarad G, Cunningham J, Rops AL, van der Vlag J, Berden JH, Moeller MJ, Holzman LB, Burgess RW, Miner JH (2007) Disruption of glomerular basement membrane charge through podocyte-specific mutation of agrin does not alter glomerular permselectivity. Am J Pathol 171:139–152

    Article  PubMed  CAS  Google Scholar 

  23. Goldberg S, Harvey SJ, Cunningham J, Tryggvason K, Miner JH (2009) Glomerular filtration is normal in the absence of both agrin and perlecan-heparan sulfate from the glomerular basement membrane. Nephrol Dial Transplant 24:2044–2051

    Article  PubMed  CAS  Google Scholar 

  24. Bullock SL, Fletcher JM, Beddington RS, Wilson VA (1998) Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase. Genes Dev 12:1894–1906

    Article  PubMed  CAS  Google Scholar 

  25. Steer DL, Shah MM, Bush KT, Stuart RO, Sampogna RV, Meyer TN, Schwesinger C, Bai X, Esko JD, Nigam SK (2004) Regulation of ureteric bud branching morphogenesis by sulfated proteoglycans in the developing kidney. Dev Biol 272:310–327

    Article  PubMed  CAS  Google Scholar 

  26. Kinnunen AI, Sormunen R, Elamaa H, Seppinen L, Miller RT, Ninomiya Y, Janmey PA, Pihlajaniemi T (2011) Lack of collagen XVIII long isoforms affects kidney podocytes while the short form is needed in the proximal tubular basement membrane. J Biol Chem 286:7755–7764

    Article  PubMed  CAS  Google Scholar 

  27. Kanwar YS, Wada J, Lin S, Danesh FR, Chugh SS, Yang Q, Banerjee T, Lomasney JW (2004) Update of extracellular matrix, its receptors, and cell adhesion molecules in mammalian nephrogenesis. Am J Physiol Ren Physiol 286:F202–F215

    Article  CAS  Google Scholar 

  28. Sakai T, Larsen M, Yamada KM (2003) Fibronectin requirement in branching morphogenesis. Nature 423:876–881

    Article  PubMed  CAS  Google Scholar 

  29. Linton JM, Martin GR, Reichardt LF (2007) The ECM protein nephronectin promotes kidney development via integrin alpha8beta1-mediated stimulation of Gdnf expression. Development 134:2501–2509

    Article  PubMed  CAS  Google Scholar 

  30. Kreidberg JA, Symons JM (2000) Integrins in kidney development, function, and disease. Am J Physiol Ren Physiol 279:F233–F242

    CAS  Google Scholar 

  31. Chen D, Roberts R, Pohl M, Nigam S, Kreidberg J, Wang Z, Heino J, Ivaska J, Coffa S, Harris RC, Pozzi A, Zent R (2004) Differential expression of collagen- and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis. Am J Physiol Ren Physiol 287:F602–F611

    Article  CAS  Google Scholar 

  32. Pozzi A, Jarad G, Moeckel GW, Coffa S, Zhang X, Gewin L, Eremina V, Hudson BG, Borza DB, Harris RC, Holzman LB, Phillips CL, Fassler R, Quaggin SE, Miner JH, Zent R (2008) Beta1 integrin expression by podocytes is required to maintain glomerular structural integrity. Dev Biol 316:288–301

    Article  PubMed  CAS  Google Scholar 

  33. Kanasaki K, Kanda Y, Palmsten K, Tanjore H, Lee SB, Lebleu VS, Gattone VH Jr, Kalluri R (2008) Integrin beta1-mediated matrix assembly and signaling are critical for the normal development and function of the kidney glomerulus. Dev Biol 313:584–593

    Article  PubMed  CAS  Google Scholar 

  34. Wu W, Kitamura S, Truong DM, Rieg T, Vallon V, Sakurai H, Bush KT, Vera DR, Ross RS, Nigam SK (2009) {beta}1-Integrin is required for kidney collecting duct morphogenesis and maintenance of renal function. Am J Physiol Ren Physiol 297:F210–F217

    Article  CAS  Google Scholar 

  35. Zhang X, Mernaugh G, Yang DH, Gewin L, Srichai MB, Harris RC, Iturregui JM, Nelson RD, Kohan DE, Abrahamson D, Fassler R, Yurchenco P, Pozzi A, Zent R (2009) beta1 integrin is necessary for ureteric bud branching morphogenesis and maintenance of collecting duct structural integrity. Development 136:3357–3366

    Article  PubMed  CAS  Google Scholar 

  36. Chen X, Moeckel G, Morrow JD, Cosgrove D, Harris RC, Fogo AB, Zent R, Pozzi A (2004) Lack of integrin alpha1beta1 leads to severe glomerulosclerosis after glomerular injury. Am J Pathol 165:617–630

    Article  PubMed  CAS  Google Scholar 

  37. Girgert R, Martin M, Kruegel J, Miosge N, Temme J, Eckes B, Muller GA, Gross O (2010) Integrin alpha2-deficient mice provide insights into specific functions of collagen receptors in the kidney. Fibrogenesis Tissue Repair 3:19

    Article  PubMed  Google Scholar 

  38. Zent R, Bush KT, Pohl ML, Quaranta V, Koshikawa N, Wang Z, Kreidberg JA, Sakurai H, Stuart RO, Nigam SK (2001) Involvement of laminin binding integrins and laminin-5 in branching morphogenesis of the ureteric bud during kidney development. Dev Biol 238:289–302

    Article  PubMed  CAS  Google Scholar 

  39. Sugawara K, Tsuruta D, Ishii M, Jones JC, Kobayashi H (2008) Laminin-332 and −511 in skin. Exp Dermatol 17:473–480

    Article  PubMed  CAS  Google Scholar 

  40. Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC, Jaenisch R (1996) Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 122:3537–3547

    PubMed  CAS  Google Scholar 

  41. Cebrian C, Borodo K, Charles N, Herzlinger DA (2004) Morphometric index of the developing murine kidney. Dev Dyn 231:601–608

    Article  PubMed  Google Scholar 

  42. Sachs N, Kreft M, van den Bergh Weerman MA, Beynon AJ, Peters TA, Weening JJ, Sonnenberg A (2006) Kidney failure in mice lacking the tetraspanin CD151. J Cell Biol 175:33–39

    Article  PubMed  CAS  Google Scholar 

  43. Liu Y, Chattopadhyay N, Qin S, Szekeres C, Vasylyeva T, Mahoney ZX, Taglienti M, Bates CM, Chapman HA, Miner JH, Kreidberg JA (2009) Coordinate integrin and c-Met signaling regulate Wnt gene expression during epithelial morphogenesis. Development 136:843–853

    Article  PubMed  CAS  Google Scholar 

  44. Kikkawa Y, Sanzen N, Fujiwara H, Sonnenberg A, Sekiguchi K (2000) Integrin binding specificity of laminin-10/11: laminin-10/11 are recognized by alpha 3 beta 1, alpha 6 beta 1 and alpha 6 beta 4 integrins. J Cell Sci 113(Pt 5):869–876

    PubMed  CAS  Google Scholar 

  45. Kikkawa Y, Yu H, Genersch E, Sanzen N, Sekiguchi K, Fassler R, Campbell KP, Talts JF, Ekblom P (2004) Laminin isoforms differentially regulate adhesion, spreading, proliferation, and ERK activation of beta1 integrin-null cells. Exp Cell Res 300:94–108

    Article  PubMed  CAS  Google Scholar 

  46. Margadant C, Charafeddine RA, Sonnenberg A (2010) Unique and redundant functions of integrins in the epidermis. FASEB J 24:4133–4152

    Article  PubMed  CAS  Google Scholar 

  47. Georges-Labouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A, Le Meur M (1996) Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet 13:370–373

    Article  PubMed  CAS  Google Scholar 

  48. De Arcangelis A, Mark M, Kreidberg J, Sorokin L, Georges-Labouesse E (1999) Synergistic activities of alpha3 and alpha6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse. Development 126:3957–3968

    PubMed  Google Scholar 

  49. Falk M, Salmivirta K, Durbeej M, Larsson E, Ekblom M, Vestweber D, Ekblom P (1996) Integrin alpha 6B beta 1 is involved in kidney tubulogenesis in vitro. J Cell Sci 109(Pt 12):2801–2810

    PubMed  CAS  Google Scholar 

  50. Ferletta M, Ekblom P (1999) Identification of laminin-10/11 as a strong cell adhesive complex for a normal and a malignant human epithelial cell line. J Cell Sci 112(Pt 1):1–10

    PubMed  CAS  Google Scholar 

  51. Cuesta-Estelles G, Escobedo-Rumoroso JM, Garces-Lopez L, Perez-Garcia A (1998) Epidermolysis bullosa and chronic renal failure. Nephrol Dial Transplant 13:2133–2134

    Article  PubMed  CAS  Google Scholar 

  52. Kambham N, Tanji N, Seigle RL, Markowitz GS, Pulkkinen L, Uitto J, D'Agati VD (2000) Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa. Am J Kidney Dis 36:190–196

    Article  PubMed  CAS  Google Scholar 

  53. Hartner A, Schocklmann H, Prols F, Muller U, Sterzel RB (1999) Alpha8 integrin in glomerular mesangial cells and in experimental glomerulonephritis. Kidney Int 56:1468–1480

    Article  PubMed  CAS  Google Scholar 

  54. Muller U, Wang D, Denda S, Meneses JJ, Pedersen RA, Reichardt LF (1997) Integrin alpha8beta1 is critically important for epithelial–mesenchymal interactions during kidney morphogenesis. Cell 88:603–613

    Article  PubMed  CAS  Google Scholar 

  55. Bieritz B, Spessotto P, Colombatti A, Jahn A, Prols F, Hartner A (2003) Role of alpha8 integrin in mesangial cell adhesion, migration, and proliferation. Kidney Int 64:119–127

    Article  PubMed  CAS  Google Scholar 

  56. Wada J, Kumar A, Liu Z, Ruoslahti E, Reichardt L, Marvaldi J, Kanwar YS (1996) Cloning of mouse integrin alphaV cDNA and role of the alphaV-related matrix receptors in metanephric development. J Cell Biol 132:1161–1176

    Article  PubMed  CAS  Google Scholar 

  57. Koyama N, Hayashi T, Gresik EW, Kashimata M (2009) Role of alpha 6 integrin subunit in branching morphogenesis of fetal mouse submandibular gland: investigation by mesenchyme-free epithelial culture system. J Med Invest 56(Suppl):247–249

    Article  PubMed  Google Scholar 

  58. Menko AS, Kreidberg JA, Ryan TT, Van Bockstaele E, Kukuruzinska MA (2001) Loss of alpha3beta1 integrin function results in an altered differentiation program in the mouse submandibular gland. Dev Dyn 220:337–349

    Article  PubMed  CAS  Google Scholar 

  59. Lange A, Wickstrom SA, Jakobson M, Zent R, Sainio K, Fassler R (2009) Integrin-linked kinase is an adaptor with essential functions during mouse development. Nature 461:1002–1006

    Article  PubMed  CAS  Google Scholar 

  60. Kashimata M, Gresik EW (1997) Epidermal growth factor system is a physiological regulator of development of the mouse fetal submandibular gland and regulates expression of the alpha6-integrin subunit. Dev Dyn 208:149–161

    Article  PubMed  CAS  Google Scholar 

  61. Liu K, Cheng L, Flesken-Nikitin A, Huang L, Nikitin AY, Pauli BU (2010) Conditional knockout of fibronectin abrogates mouse mammary gland lobuloalveolar differentiation. Dev Biol 346:11–24

    Article  PubMed  CAS  Google Scholar 

  62. El-Aouni C, Herbach N, Blattner SM, Henger A, Rastaldi MP, Jarad G, Miner JH, Moeller MJ, St-Arnaud R, Dedhar S, Holzman LB, Wanke R, Kretzler M (2006) Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis. J Am Soc Nephrol 17:1334–1344

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine (Division of Nephrology), Vanderbilt University Medical Center, Nashville, TN, USA

    Sijo Mathew, Xiwu Chen, Ambra Pozzi & Roy Zent

  2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    Ambra Pozzi & Roy Zent

  3. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    Roy Zent

  4. Department of Medicine, Veterans Administration Hospital, Nashville, TN, USA

    Ambra Pozzi & Roy Zent

  5. Division of Nephrology and Hypertension, Vanderbilt University, Room C3210 MCN, Medical Center North, Nashville, TN, 27232, USA

    Ambra Pozzi & Roy Zent

Authors
  1. Sijo Mathew
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiwu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ambra Pozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roy Zent
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ambra Pozzi or Roy Zent.

Additional information

Sijo Mathew and Xiwu Chen contributed equally to this manuscript

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mathew, S., Chen, X., Pozzi, A. et al. Integrins in renal development. Pediatr Nephrol 27, 891–900 (2012). https://doi.org/10.1007/s00467-011-1890-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-011-1890-1

Keywords

Search

Navigation