The proximal tubular cell, a key player in renal damage

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Abstract

A decline in renal function is associated with the degree of proteinuria and with histological findings of glomerulosclerosis and interstitial fibrosis. Proteinuria is not only a marker of renal damage, but ultrafiltered proteins can be toxic to the kidney, thereby contributing to tubulo-interstitial damage. In this project, we evaluated the effects of albumin-bound fatty acids on renal damage in a model of persistent proteinuria, overload proteinuria, in 2 different species: the classical rat overload proteinuria and the salamander axolotl. The salamander kidney possesses normal closed nephrons but also open nephrons in which the tubule connects to the coloemic cavity. Injection of proteins in this cavity will lead to direct protein loading of the open tubules without possible protein modifications due to passage through the circulation that might occur in the rat model. We showed in both species that the contribution of albumin-bound oleic acid to the initiation and progression of chronic renal damage was only minor. Furthermore, we evaluated the contribution of tubular cells in the inflammatory and fibrotic response. For the contribution of tubular cells we specifically studied Kidney Injury Molecule-1 (KIM-1). KIM-1 is a transmembrane tubular protein with unknown function, that is non-detectable in normal kidneys, but is markedly induced after renal injury. In addition, KIM-1 ectodomain shedding into urine has been reported. We showed KIM-1 induction in experimental overload proteinuria and in different proteinuric and fibrotic human renal diseases. KIM-1 was primarily expressed at luminal sides of dedifferentiated proximal tubules in areas with fibrosis and inflammation. Furthermore, urinary KIM-1 levels were related to tubular KIM-1, inflammation and showed an inverse association with renal function but there was no significant association with proteinuria. In renal transplant recipients urinary KIM-1 predicted renal function decline. The results indicate that the extent of tubular damage is reflected by KIM-1 expression and shedding. Future studies should address whether urinary KIM-1 excretion can also predict renal function decline in proteinuric nephropathies other than those observed in transplanted kidneys and should clarify the functional role of KIM-1.
Original languageEnglish
QualificationDoctor of Philosophy
Supervisors/Advisors
  • Gans, Rijk, Supervisor
  • Bakker, Stephan, Supervisor
Publisher
Print ISBNs9789036733335
Publication statusPublished - 2008

Keywords

  • Proefschriften (vorm)
  • Nierbuisjes, Beschadiging
  • urologie

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