The glomerular basement membrane as a barrier to albumin


The glomerular basement membrane (GBM) is the central, non-cellular layer of the glomerular filtration barrier that is situated between the two cellular components—fenestrated endothelial cells and interdigitated podocyte foot processes. The GBM is composed primarily of four types of extracellular matrix macromolecule—laminin-521, type IV collagen α3α4α5, the heparan sulphate proteoglycan agrin, and nidogen—which produce an interwoven meshwork thought to impart both size-selective and charge-selective properties. Although the composition and biochemical nature of the GBM have been known for a long time, the functional importance of the GBM versus that of podocytes and endothelial cells for establishing the glomerular filtration barrier to albumin is still debated. Together with findings from genetic studies in mice, the discoveries of four human mutations affecting GBM components in two inherited kidney disorders, Alport syndrome and Pierson syndrome, support essential roles for the GBM in glomerular permselectivity. Here, we explain in detail the proposed mechanisms whereby the GBM can serve as the major albumin barrier and discuss possible approaches to circumvent GBM defects associated with loss of permselectivity.

Key Points

  • The glomerular basement membrane (GBM) is the extracellular matrix component of the glomerular filtration barrier; it is flanked by the podocyte and glomerular endothelial cell layers

  • The major GBM components are laminin-521, type IV collagen α3α4α5, nidogen, and the heparan sulphate proteoglycan agrin

  • Mutations in COL4 genes that result in absence of the type IV collagen α3α4α5 network cause Alport syndrome, a hereditary nephritis accompanied by hearing defects

  • Mutations in laminin β2 (LAMB2) cause Pierson syndrome, a congenital nephrotic syndrome with associated eye and neurologic abnormalities

  • Studies using mouse models of Pierson and Alport syndromes have shown that the defective GBM is more permeable to macromolecules than is the normal GBM, suggesting that it has a role in permselectivity

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The components of the GBM.
Figure 2: Mutations in Lamb2 result in albuminuria in a mouse model of Pierson syndrome.
Figure 3: Mutations in the genes encoding type IV collagen α3, α4, or α5 result in albuminuria in a mouse model of Alport syndrome.


  1. 1

    Miner, J. H. Organogenesis of the kidney glomerulus: focus on the glomerular basement membrane. Organogenesis 7, 75–82 (2011).

    Article  Google Scholar 

  2. 2

    Yurchenco, P. D. & Patton, B. L. Developmental and pathogenic mechanisms of basement membrane assembly. Curr. Pharm. Des. 15, 1277–1294 (2009).

    CAS  Article  Google Scholar 

  3. 3

    Miner, J. H. Building the glomerulus: a matricentric view. J. Am. Soc. Nephrol. 16, 857–861 (2005).

    CAS  Article  Google Scholar 

  4. 4

    Kruegel, J., Rubel, D. & Gross, O. Alport syndrome—insights from basic and clinical research. Nat. Rev. Nephrol. 9, 170–178 (2013).

    CAS  Article  Google Scholar 

  5. 5

    Matejas, V. et al. Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum. Hum. Mutat. 31, 992–1002 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Jefferson, J. A., Shankland, S. J. & Pichler, R. H. Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int. 74, 22–36 (2008).

    CAS  Article  Google Scholar 

  7. 7

    de Boer, I. H. et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 305, 2532–2539 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Farquhar, M. G. The glomerular basement membrane: not gone, just forgotten. J. Clin. Invest. 116, 2090–2093 (2006).

    CAS  Article  Google Scholar 

  9. 9

    Miner, J. H. The glomerular basement membrane. Exp. Cell Res. 318, 973–978 (2012).

    CAS  Article  Google Scholar 

  10. 10

    St John, P. L. & Abrahamson, D. R. Glomerular endothelial cells and podocytes jointly synthesize laminin-1 and -11 chains. Kidney Int. 60, 1037–1046 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Eremina, V. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Farquhar, M. G. Editorial: The primary glomerular filtration barrier—basement membrane or epithelial slits? Kidney Int. 8, 197–211 (1975).

    CAS  Article  Google Scholar 

  13. 13

    Farquhar, M. G. & Palade, G. E. Glomerular permeability. II. Ferritin transfer across the glomerular capillary wall in nephrotic rats. J. Exp. Med. 114, 699–716 (1961).

    CAS  Article  Google Scholar 

  14. 14

    Farquhar, M. G., Wissig, S. L. & Palade, G. E. Glomerular permeability. I. Ferritin transfer across the normal glomerular capillary wall. J. Exp. Med. 113, 47–66 (1961).

    CAS  Article  Google Scholar 

  15. 15

    Brenner, B. M., Hostetter, T. H. & Humes, H. D. Molecular basis of proteinuria of glomerular origin. N. Engl. J. Med. 298, 826–833 (1978).

    CAS  Article  Google Scholar 

  16. 16

    Miner, J. H. & Yurchenco, P. D. Laminin functions in tissue morphogenesis. Annu. Rev. Cell. Dev. Biol. 20, 255–284 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Paulsson, M. Basement membrane proteins: structure, assembly, and cellular interactions. Crit. Rev. Biochem. Molec. Biol. 27, 93–127 (1992).

    CAS  Article  Google Scholar 

  18. 18

    Ekblom, P. & Timpl, R. Cell-to-cell contact and extracellular matrix. A multifaceted approach emerging. Curr. Opin. Cell Biol. 8, 599–601 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Yurchenco, P. D. & Cheng, Y. S. Self-assembly and calcium-binding sites in laminin. A three-arm interaction model. J. Biol. Chem. 268, 17286–17299 (1993).

    CAS  PubMed  Google Scholar 

  20. 20

    Cheng, Y. S., Champliaud, M. F., Burgeson, R. E., Marinkovich, M. P. & Yurchenco, P. D. Self-assembly of laminin isoforms. J. Biol. Chem. 272, 31525–31532 (1997).

    CAS  Article  Google Scholar 

  21. 21

    Timpl, R. et al. Structure and function of laminin LG modules. Matrix Biol. 19, 309–317 (2000).

    CAS  Article  Google Scholar 

  22. 22

    Colognato, H. & Yurchenco, P. D. Form and function: the laminin family of heterotrimers. Dev. Dyn. 218, 213–234 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Henry, M. D. & Campbell, K. P. Dystroglycan inside and out. Curr. Opin. Cell Biol. 11, 602–607 (1999).

    CAS  Article  Google Scholar 

  24. 24

    Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Kreidberg, J. A. et al. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 122, 3537–3547 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Kikkawa, Y., Sanzen, N. & Sekiguchi, K. Isolation and characterization of laminin-10/11 secreted by human lung carcinoma cells. laminin-10/11 mediates cell adhesion through integrin alpha3 beta1. J. Biol. Chem. 273, 15854–15859 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Kikkawa, Y., Virtanen, I. & Miner, J. H. Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the glomerular basement membrane. J. Cell Biol. 161, 187–196 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Wizemann, H. et al. Distinct requirements for heparin and alpha-dystroglycan binding revealed by structure-based mutagenesis of the laminin alpha2 LG4-LG5 domain pair. J. Mol. Biol. 332, 635–642 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Jarad, G., Pippin, J. W., Shankland, S. J., Kreidberg, J. A. & Miner, J. H. Dystroglycan does not contribute significantly to kidney development or function, in health or after injury. Am. J. Physiol. Renal Physiol. 300, F811–F820 (2011).

    CAS  Article  Google Scholar 

  30. 30

    Chen, Y. M. & Miner, J. H. Glomerular basement membrane and related glomerular disease. Transl. Res. 160, 291–297 (2012).

    CAS  Article  Google Scholar 

  31. 31

    Colognato, H., Winkelmann, D. A. & Yurchenco, P. D. Laminin polymerization induces a receptor-cytoskeleton network. J. Cell Biol. 145, 619–631 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Poschl, E. et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628 (2004).

    Article  Google Scholar 

  33. 33

    Smyth, N. et al. 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 (1999).

    CAS  Article  Google Scholar 

  34. 34

    Vanacore, R. et al. A sulfilimine bond identified in collagen IV. Science 325, 1230–1234 (2009).

    CAS  Article  Google Scholar 

  35. 35

    Hudson, B. G. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family. J. Am. Soc. Nephrol. 15, 2514–2527 (2004).

    Article  Google Scholar 

  36. 36

    Miner, J. H. Developmental biology of glomerular basement membrane components. Curr. Opin. Nephrol. Hypertens. 7, 13–19 (1998).

    CAS  Article  Google Scholar 

  37. 37

    Gunwar, S. et al. Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of alpha3, alpha4, and alpha5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J. Biol. Chem. 273, 8767–8775 (1998).

    CAS  Article  Google Scholar 

  38. 38

    Kohfeldt, E., Sasaki, T., Gohring, W. & Timpl, R. Nidogen-2: a new basement membrane protein with diverse binding properties. J. Mol. Biol. 282, 99–109 (1998).

    CAS  Article  Google Scholar 

  39. 39

    Timpl, R. Structure and biological activity of basement membrane proteins. Eur. J. Biochem. 180, 487–502 (1989).

    CAS  Article  Google Scholar 

  40. 40

    Miosge, N., Sasaki, T. & Timpl, R. Evidence of nidogen-2 compensation for nidogen-1 deficiency in transgenic mice. Matrix Biol. 21, 611–621 (2002).

    CAS  Article  Google Scholar 

  41. 41

    Miosge, N. et al. Ultrastructural colocalization of nidogen-1 and nidogen-2 with laminin-1 in murine kidney basement membranes. Histochem. Cell Biol. 113, 115–124 (2000).

    CAS  Article  Google Scholar 

  42. 42

    Schymeinsky, J. et al. 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 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Murshed, M. et al. The absence of nidogen 1 does not affect murine basement membrane formation. Mol. Cell. Biol. 20, 7007–7012 (2000).

    CAS  Article  Google Scholar 

  44. 44

    Bader, B. L. et al. Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice. Mol. Cell. Biol. 25, 6846–6856 (2005).

    CAS  Article  Google Scholar 

  45. 45

    Groffen, A. J. et al. Agrin is a major heparan sulfate proteoglycan in the human glomerular basement membrane. J. Histochem. Cytochem. 46, 19–27 (1998).

    CAS  Article  Google Scholar 

  46. 46

    Harvey, S. J. et al. Disruption of glomerular basement membrane charge through podocyte-specific mutation of agrin does not alter glomerular permselectivity. Am. J. Pathol. 171, 139–152 (2007).

    CAS  Article  Google Scholar 

  47. 47

    Rennke, H. G., Cotran, R. S. & Venkatachalam, M. A. Role of molecular charge in glomerular permeability. Tracer studies with cationized ferritins. J. Cell Biol. 67, 638–646 (1975).

    CAS  Article  Google Scholar 

  48. 48

    Bezakova, G. & Ruegg, M. A. New insights into the roles of agrin. Nat. Rev. Mol. Cell Biol. 4, 295–308 (2003).

    CAS  Article  Google Scholar 

  49. 49

    Park, J. E., Keller, G. A. & Ferrara, N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol. Cell 4, 1317–1326 (1993).

    CAS  Article  Google Scholar 

  50. 50

    Goldberg, S., Harvey, S. J., Cunningham, J., Tryggvason, K. & Miner, J. H. 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 (2009).

    CAS  Article  Google Scholar 

  51. 51

    Morita, H. et al. Heparan sulfate of perlecan is involved in glomerular filtration. J. Am. Soc. Nephrol. 16, 1703–1710 (2005).

    CAS  Article  Google Scholar 

  52. 52

    Pierson, M., Cordier, J., Hervouuet, F. & Rauber, G. An unusual congenital and familial congenital malformative combination involving the eye and kidney. J. Genet. Hum. 12, 184–213 (1963).

    CAS  PubMed  Google Scholar 

  53. 53

    Zenker, M. et al. Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum. Mol. Genet. 13, 2625–2632 (2004).

    CAS  Article  Google Scholar 

  54. 54

    Zenker, M., Pierson, M., Jonveaux, P. & Reis, A. Demonstration of two novel LAMB2 mutations in the original Pierson syndrome family reported 42 years ago. Am. J. Med. Genet. A 138, 73–74 (2005).

    Article  Google Scholar 

  55. 55

    Lehnhardt, A. et al. Pierson syndrome in an adolescent girl with nephrotic range proteinuria but a normal GFR. Pediatr. Nephrol. 27, 865–868 (2012).

    Article  Google Scholar 

  56. 56

    Kagan, M., Cohen, A. H., Matejas, V., Vlangos, C. & Zenker, M. A milder variant of Pierson syndrome. Pediatr. Nephrol. 23, 323–327 (2008).

    Article  Google Scholar 

  57. 57

    Hasselbacher, K. et al. Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders. Kidney Int. 70, 1008–1012 (2006).

    CAS  Article  Google Scholar 

  58. 58

    Chen, Y. M., Kikkawa, Y. & Miner, J. H. A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion. J. Am. Soc. Nephrol. 22, 849–858 (2011).

    CAS  Article  Google Scholar 

  59. 59

    Purvis, A. & Hohenester, E. Laminin network formation studied by reconstitution of ternary nodes in solution. J. Biol. Chem. 287, 44270–44277 (2012).

    CAS  Article  Google Scholar 

  60. 60

    Noakes, P. G. et al. The renal glomerulus of mice lacking s-laminin/laminin beta 2: nephrosis despite molecular compensation by laminin beta 1. Nat. Genet. 10, 400–406 (1995).

    CAS  Article  Google Scholar 

  61. 61

    Noakes, P. G., Gautam, M., Mudd, J., Sanes, J. R. & Merlie, J. P. Aberrant differentiation of neuromuscular junctions in mice lacking s-laminin/laminin beta 2. Nature 374, 258–262 (1995).

    CAS  Article  Google Scholar 

  62. 62

    Jarad, G., Cunningham, J., Shaw, A. S. & Miner, J. H. Proteinuria precedes podocyte abnormalities in Lamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier. J. Clin. Invest. 116, 2272–2279 (2006).

    CAS  Article  Google Scholar 

  63. 63

    Ryan, G. B. & Karnovsky, M. J. Distribution of endogenous albumin in the rat glomerulus: role of hemodynamic factors in glomerular barrier function. Kidney Int. 9, 36–45 (1976).

    CAS  Article  Google Scholar 

  64. 64

    Wartiovaara, J. et al. Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. J. Clin. Invest. 114, 1475–1483 (2004).

    CAS  Article  Google Scholar 

  65. 65

    Noone, D. & Licht, C. An update on the pathomechanisms and future therapies of Alport syndrome. Pediatr. Nephrol. 28, 1025–1036 (2013).

    Article  Google Scholar 

  66. 66

    Abrahamson, D. R., Hudson, B. G., Stroganova, L., Borza, D. B. & St John, P. L. Cellular origins of type IV collagen networks in developing glomeruli. J. Am. Soc. Nephrol. 20, 1471–1479 (2009).

    CAS  Article  Google Scholar 

  67. 67

    Abrahamson, D. R. et al. Laminin compensation in collagen alpha3(IV) knockout (Alport) glomeruli contributes to permeability defects. J. Am. Soc. Nephrol. 18, 2465–2472 (2007).

    CAS  Article  Google Scholar 

  68. 68

    Gross, O. et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3-knockout mice with Alport syndrome. Kidney Int. 63, 438–446 (2003).

    CAS  Article  Google Scholar 

  69. 69

    Gross, O. et al. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 81, 494–501 (2012).

    CAS  Article  Google Scholar 

  70. 70

    Wyss, H. M. et al. Biophysical properties of normal and diseased renal glomeruli. Am. J. Physiol. Cell Physiol. 300, C397–C405 (2011).

    CAS  Article  Google Scholar 

  71. 71

    Meehan, D. T. et al. Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease. Kidney Int. 76, 968–976 (2009).

    Article  Google Scholar 

  72. 72

    Smithies, O. Why the kidney glomerulus does not clog: a gel permeation/diffusion hypothesis of renal function. Proc. Natl Acad. Sci. USA 100, 4108–4113 (2003).

    CAS  Article  Google Scholar 

  73. 73

    Suh, J. H., Jarad, G., Vandevoorde, R. G. & Miner, J. H. Forced expression of laminin beta1 in podocytes prevents nephrotic syndrome in mice lacking laminin beta2, a model for Pierson syndrome. Proc. Natl Acad. Sci. USA 108, 15348–15353 (2011).

    CAS  Article  Google Scholar 

  74. 74

    Chen, Y. M. et al. Laminin β2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J. Am. Soc. Nephrol.

  75. 75

    Kikkawa, Y. & Miner, J. H. Molecular dissection of laminin alpha 5 in vivo reveals separable domain-specific roles in embryonic development and kidney function. Dev. Biol. 296, 265–277 (2006).

    CAS  Article  Google Scholar 

  76. 76

    Brinkkoetter, P. T., Ising, C. & Benzing, T. The role of the podocyte in albumin filtration. Nat. Rev. Nephrol.

  77. 77

    Faul, C., Asanuma, K., Yanagida-Asanuma, E., Kim, K. & Mundel, P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 17, 428–437 (2007).

    CAS  Article  Google Scholar 

Download references


The authors are supported by NIH grants R01DK078314, R21DK095419, and P30DK079333 and by a grant from the Alport Syndrome Foundation. J. H. Suh is also supported by NIH training grant T32DK007126.

Author information




The authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Jeffrey H. Miner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Suh, J., Miner, J. The glomerular basement membrane as a barrier to albumin. Nat Rev Nephrol 9, 470–477 (2013).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing