Document Detail


Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion.
MedLine Citation:
PMID:  20237235     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Connective tissue growth factor (CTGF) plays a key role in renal fibrosis. Urinary CTGF is elevated in various renal diseases and may have biomarker potential. However, it is unknown which processes contribute to elevated urinary CTGF levels. Thus far, urinary CTGF was considered to reflect renal expression. We investigated how tubular dysfunction affects urinary CTGF levels. To study this, we administered recombinant CTGF intravenously to rodents. We used both full-length CTGF and the NH(2)-terminal fragment, since the NH(2)-fragment is the predominant form detected in urine. Renal CTGF extraction, determined by simultaneous arterial and renal vein sampling, was 18 +/- 3% for full-length CTGF and 21 +/- 1% for the NH(2)-fragment. Fractional excretion was very low for both CTGFs (0.02 +/- 0.006% and 0.10 +/- 0.02%, respectively), indicating that >99% of the extracted CTGF was metabolized by the kidney. Immunohistochemistry revealed extensive proximal tubular uptake of CTGF in apical endocytic vesicles and colocalization with megalin. Urinary CTGF was elevated in megalin- and cubilin-deficient mice but not in cubilin-deficient mice. Inhibition of tubular reabsorption by Gelofusine reduced renal uptake of CTGF and increased urinary CTGF. In healthy volunteers, Gelofusine also induced an increase of urinary CTGF excretion, comparable to the increase of beta(2)-microglobulin excretion (r = 0.99). Furthermore, urinary CTGF correlated with beta(2)-microglobulin (r = 0.85) in renal disease patients (n = 108), and only beta(2)-microglobulin emerged as an independent determinant of urinary CTGF. Thus filtered CTGF is normally reabsorbed almost completely in proximal tubules via megalin, and elevated urinary CTGF may largely reflect proximal tubular dysfunction.
Authors:
Karin G Gerritsen; Hilde P Peters; Tri Q Nguyen; Maarten P Koeners; Jack F Wetzels; Jaap A Joles; Erik I Christensen; Pierre J Verroust; Dongxia Li; Noelynn Oliver; Leon Xu; Robbert J Kok; Roel Goldschmeding
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-17
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  298     ISSN:  1522-1466     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-21     Completed Date:  2010-06-14     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F1457-64     Citation Subset:  IM    
Affiliation:
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. K.G.F.Gerritsen@umcutrecht.nl
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Markers / blood,  urine
Connective Tissue Growth Factor / administration & dosage,  blood,  pharmacokinetics,  urine*
Cross-Sectional Studies
Endocytosis
Glomerular Filtration Rate
Humans
Infusions, Parenteral
Injections, Intravenous
Kidney Diseases / metabolism*,  physiopathology
Kidney Tubules, Proximal / drug effects,  metabolism*,  physiopathology
LDL-Receptor Related Protein 2 / deficiency,  genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Peptide Fragments / administration & dosage,  blood,  pharmacokinetics,  urine*
Polygeline / administration & dosage
Rats
Rats, Inbred WKY
Receptors, Cell Surface / deficiency,  genetics
Recombinant Fusion Proteins / urine
beta 2-Microglobulin / urine
Chemical
Reg. No./Substance:
0/Biological Markers; 0/CTGF protein, human; 0/Ctgf protein, mouse; 0/LDL-Receptor Related Protein 2; 0/Lrp2 protein, mouse; 0/Peptide Fragments; 0/Receptors, Cell Surface; 0/Recombinant Fusion Proteins; 0/beta 2-Microglobulin; 0/intrinsic factor-cobalamin receptor; 139568-91-5/Connective Tissue Growth Factor; 9015-56-9/Polygeline

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