Dtsch Med Wochenschr 2010; 135(24): 1232-1236
DOI: 10.1055/s-0030-1255142
Übersicht | Review article
Nephrologie
© Georg Thieme Verlag KG Stuttgart · New York

Neue Erkenntnisse zur glomerulären Struktur

Novel insights into the glomerular structureM. J. Moeller1
  • 1Medizinische Klinik 2, Nephrologie und Klinische Immunologie, Universitätsklinikum der RWTH Aachen
Further Information

Publication History

eingereicht: 31.1.2010

akzeptiert: 20.5.2010

Publication Date:
08 June 2010 (online)

Zusammenfassung

Während der letzten Jahre hat es bedeutende Forschritte im Verständnis des Aufbaus und der Pathomechanismen des renalen Glomerulus gegeben. In dieser Übersichtsarbeit wird eine Auswahl neuer Aspekte beleuchtet: 1.) Die Funktionsweise der glomerulären Filtrationsbarriere ist bis heute noch nicht gänzlich aufgeklärt, obwohl mittlerweile der anatomische Aufbau auch auf molekularer Ebene gut bekannt ist. 2.) Im Glomerulus vermittelt vascular endothelial growth factor (VEGF) ein von den Podozyten ausgehendes, räumliches Signal, das entscheidend den Aufbau des Glomerulus beeinflusst. 3.) Die Theorie des subpodocyte space liefert eine neue Erklärung für den effektiven Rücktransport von VEGF gegen den Filtrationsstrom von den Podozyten zu den Endothelzellen. 4.) Neu entwickelte transgene Mausmodelle haben nach den Podozyten nun auch die Parietalzellen einer systematischen funktionellen Erforschung zugänglich gemacht. Parietalzellen stellen möglicherweise eine intrarenale Progenitorzellpopulation für die Regeneration von Podozyten dar. 5.) Parietalzellen spielen eine bislang unterschätzte Rolle bei verschiedenen glomerulären Erkrankungen. So werden zelluläre Halbmonde im Rahmen einer rapid progressiven Glomerulonephritis vor allem von glomerulären Parietalzellen ausgebildet.

Abstract

In recent years, significant progress has been made in understanding the structure and pathomechanisms of the glomerulus of the kidney. Some of these more recent advances and open questions are discussed in this review: 1.) The functioning of the glomerular filter still remains incompletely understood, although the microanatomy and molecular biology of the glomerular filter has been investigated in great detail. 2.) Vascular endothelial growth factor (VEGF) has been shown to mediate spacial clues that are essential for the polarized distribution of the cells within the glomerulus. 3.) A novel theory of the subpodocyte space offers a novel explanation for the flux of VEGF from the podocytes against the bulk flow of the filtrate to the glomerular endothelial cells. 4.) Novel transgenic mouse models have enabled us to investigate the functional role not only of podocytes but more recently also of parietal cells which might serve as an intrarenal progenitor cell population. 5.) Parietal cells play a so far under-recognized role in various glomerular diseases. In rapid progressive glomerulonephritis, cellular crescents originate predominantly from parietal cells.

Literatur

  • 1 Appel D, Kershaw D B, Smeets B. et al . Recruitment of podocytes from glomerular parietal epithelial cells.  J Am Soc Nephrol. 2009;  20 333-343
  • 2 Comper W D, Hilliard L M, Nikolic-Paterson D J, Russo L M. Disease-dependent mechanisms of albuminuria.  Am J Physiol Renal Physiol. 2008;  295 F1589-600
  • 3 Deen W M, Bohrer M P, Brenner B M. Macromolecule transport across glomerular capillaries: application of pore theory.  Kidney Int. 1979;  16 353-365
  • 4 Duffield J S, Tipping P G, Kipari T. et al . Conditional ablation of macrophages halts progression of crescentic glomerulonephritis.  Am J Pathol. 2005;  167 1207-1219
  • 5 Eremina V, Jefferson J A, Kowalewska J. et al . VEGF inhibition and renal thrombotic microangiopathy.  N Engl J Med. 2008;  358 1129-1136
  • 6 Eremina V, Sood M, Haigh J. et al . Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.  J Clin Invest. 2003;  111 707-716
  • 7 Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T, Risau W. Vascular endothelial growth factor induces endothelial fenestrations in vitro.  J Cell Biol. 1998;  140 947-959
  • 8 Fries J W, Sandstrom D J, Meyer T W, Rennke H G. Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat.  Lab Invest. 1989;  60 205-218
  • 9 Fujigaki Y, Nagase M, Kobayasi S, Hidaka S, Shimomura M, Hishida A. Intra-GBM site of the functional filtration barrier for endogenous proteins in rats.  Kidney Int. 1993;  43 567-574
  • 10 Gibson I W, Gardiner D S, Downie I, Downie T T, More I A, Lindop G B. A comparative study of the glomerular peripolar cell and the renin-secreting cell in twelve mammalian species.  Cell Tissue Res. 1994;  277 385-390
  • 11 Hakroush S, Moeller M J, Theilig F. et al . Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease.  Am J Pathol. 2009;  175 1883-1895
  • 12 Haraldsson B, Barisoni L, Quaggin S E. Reply to: VEGF inhibition and renal thrombotic microangiopathy.  New Engl J Med. 2008;  359 205-207
  • 13 Haraldsson B, Nystrom J, Deen W M. Properties of the glomerular barrier and mechanisms of proteinuria.  Physiol Rev. 2008;  88 451-487
  • 14 Huber T B, Benzing T. The slit diaphragm: a signaling platform to regulate podocyte function.  Curr Opin Nephrol Hypertens. 2005;  14 211-216
  • 15 Kamba T, Tam B Y, Hashizume H. et al . VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.  Am J Physiol Heart Circ Physiol. 2006;  290 H560-576
  • 16 Kriz W, Kaissling B. Structural organization of the mammalian kidney. In: Seldin DW, Giebisch G The Kidney: Physiology and Pathophysiology. New York: Raven Press; 1992: 707-777
  • 17 Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-insights from animal models.  Kidney Int. 2005;  67 404-419
  • 18 Kriz W, Lemley K V. The role of the podocyte in glomerulosclerosis.  Curr Opin Nephrol Hypertens. 1999;  8 489-497
  • 19 LeHir M, Besse-Eschmann V. A novel mechanism of nephron loss in a murine model of crescentic glomerulonephritis.  Kidney Int. 2003;  63 591-599
  • 20 Macconi D, Sangalli F, Bonomelli M. et al . Podocyte repopulation contributes to regression of glomerular injury induced by ACE inhibition.  Am J Pathol. 2009;  174 797-807
  • 21 Moeller M J, Kovari I A, Holzman L B. Evaluation of a new tool for exploring podocyte biology: mouse Nphs1 5’ flanking region drives LacZ expression in podocytes.  J Am Soc Nephrol. 2000;  11 2306-2314
  • 22 Moeller M J, Sanden S K, Soofi A, Wiggins R C, Holzman L B. Podocyte-specific expression of cre recombinase in transgenic mice.  Genesis. 2003;  35 39-42
  • 23 Moeller M J, Soofi A, Braun G S. et al . Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization.  EMBO J. 2004;  23 3769-3779
  • 24 Moeller M J, Soofi A, Hartmann I. et al . Podocytes populate cellular crescents in a murine model of inflammatory glomerulonephritis.  J Am Soc Nephrol. 2004;  15 61-67
  • 25 Neal C R, Muston P R, Njegovan D. et al . Glomerular filtration into the subpodocyte space is highly restricted under physiological perfusion conditions.  Am J Physiol Renal Physiol. 2007;  293 F1787-1798
  • 26 Pabst R, Sterzel R B. Cell renewal of glomerular cell types in normal rats. An autoradiographic analysis.  Kidney Int. 1983;  24 626-31
  • 27 Remuzzi A, Gagliardini E, Sangalli F. et al . ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease.  Kidney Int. 2006;  69 1124-30
  • 28 Rippe B, Haraldsson B. Transport of macromolecules across microvascular walls: the two-pore theory.  Physiol Rev. 1994;  74 163-219
  • 29 Ronconi E, Sagrinati C, Angelotti M L. et al . Regeneration of glomerular podocytes by human renal progenitors.  J Am Soc Nephrol. 2009;  20 322-332
  • 30 Rostgaard J, Qvortrup K. Sieve plugs in fenestrae of glomerular capillaries – site of the filtration barrier?.  Cells Tissues Organs. 2002;  170 132-138
  • 31 Russo L M, Sandoval R M, McKee M. et al . The normal kidney filters nephrotic levels of albumin retrieved by proximal tubule cells: retrieval is disrupted in nephrotic states.  Kidney Int. 2007;  71 504-513
  • 32 Ryan G B, Karnovsky M J. Distribution of endogenous albumin in the rat glomerulus: role of hemodynamic factors in glomerular barrier function.  Kidney Int. 1976;  9 36-45
  • 33 Shigehara T, Zaragoza C, Kitiyakara C. et al . Inducible podocyte-specific gene expression in transgenic mice.  J Am Soc Nephrol. 2003;  14 1998-2003
  • 34 Smeets B, Angelotti M L, Rizzo P. et al . Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis.  J Am Soc Nephrol. 2009;  20 2593-2603
  • 35 Smeets B, Uhlig S, Fuss A. et al . Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells.  J Am Soc Nephrol. 2009;  20 2604-2615
  • 36 Smithies O. Why the kidney glomerulus does not clog: a gel permeation/diffusion hypothesis of renal function.  Proc Nat Acad Sci. 2003;  100 4108-4113
  • 37 Tryggvason K, Wartiovaara J. How does the kidney filter plasma?.  Physiology (Bethesda). 2005;  20 96-101
  • 38 Wartiovaara J, Ofverstedt L G, Khoshnoodi J. et al . Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography.  J Clin Invest. 2004;  114 1475-1483
  • 39 Wharram B L, Goyal M, Wiggins J E. et al . Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.  J Am Soc Nephrol. 2005;  16 2941-2952
  • 40 Wolgast M, Kallskog O, Wahlstrom H. Characteristics of the glomerular capillary membrane of the rat kidney as a hydrated gel. II. On the validity of the model.  Acta Physiol Scand. 1996;  158 225-232
  • 41 Wong M A, Cui S, Quaggin S E. Identification and characterization of a glomerular-specific promoter from the human nephrin gene.  Am J Physiol Renal Physiol. 2000;  279 F1027-1032

PD Dr. med. Marcus J. Moeller

Medizinische Klinik 2, Nephrologie und Klinische Immunologie, Universitätsklinikum der RWTH Aachen

Pauwelsstr. 30

52074 Aachen

Email: mmoeller@ukaachen.de

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