Protein load impairs factor H binding promoting complement-dependent dysfunction of proximal tubular cells

Simona Buelli, Mauro Abbate, Marina Morigi, Daniela Moioli, Cristina Zanchi, Marina Noris, Carla Zoja, Charles D. Pusey, Peter F. Zipfel, Giuseppe Remuzzi

Research output: Contribution to journalArticle

Abstract

Intrarenal complement activation plays an important role in the progression of chronic kidney disease. A key target of the activated complement cascade is the proximal tubule, a site where abnormally filtered plasma proteins and complement factors combine to promote injury. This study determined whether protein overloading of human proximal tubular cells (HK-2) in culture enhances complement activation by impairing complement regulation. Addition of albumin or transferrin to the cells incubated with diluted human serum as a source of complement caused increased apical C3 deposition. Soluble complement receptor-1 (an inhibitor of all 3 activation pathways) blocked complement deposition while the classical and lectin pathway inhibitor, magnesium chloride EGTA, was, ineffective. Media containing albumin as well as complement had additive proinflammatory effects as shown by increased fractalkine and transforming growth factor-β mRNA expression. This paralleled active C3 and C5b-9 generations, effects not shared by transferrin. Factor H, one of the main natural inhibitors of the alternative pathway, binds to heparan sulfate proteoglycans. Both the density of heparan sulfate and factor H binding were reduced with protein loading, thereby enhancing the albumin- and serum-dependent complement activation potential. Thus, protein overload reduces the ability of the tubule cell to bind factor H and counteract complement activation, effects instrumental to renal disease progression.

Original languageEnglish
Pages (from-to)1050-1059
Number of pages10
JournalKidney International
Volume75
Issue number10
DOIs
Publication statusPublished - May 2009

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Complement Factor H
Complement Activation
Transferrin
Albumins
Proteins
Chemokine CX3CL1
Complement Membrane Attack Complex
Complement Receptors
Cohort Effect
Heparan Sulfate Proteoglycans
Magnesium Chloride
Heparitin Sulfate
Egtazic Acid
Transforming Growth Factors
Chronic Renal Insufficiency
Lectins
Serum Albumin
Disease Progression
Blood Proteins
Kidney

Keywords

  • Albumin
  • Chemokines
  • Complement
  • Cytokines
  • Factor H
  • Transferrin

ASJC Scopus subject areas

  • Nephrology

Cite this

Protein load impairs factor H binding promoting complement-dependent dysfunction of proximal tubular cells. / Buelli, Simona; Abbate, Mauro; Morigi, Marina; Moioli, Daniela; Zanchi, Cristina; Noris, Marina; Zoja, Carla; Pusey, Charles D.; Zipfel, Peter F.; Remuzzi, Giuseppe.

In: Kidney International, Vol. 75, No. 10, 05.2009, p. 1050-1059.

Research output: Contribution to journalArticle

Buelli, Simona ; Abbate, Mauro ; Morigi, Marina ; Moioli, Daniela ; Zanchi, Cristina ; Noris, Marina ; Zoja, Carla ; Pusey, Charles D. ; Zipfel, Peter F. ; Remuzzi, Giuseppe. / Protein load impairs factor H binding promoting complement-dependent dysfunction of proximal tubular cells. In: Kidney International. 2009 ; Vol. 75, No. 10. pp. 1050-1059.
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