Renal proximal tubular dysfunction is a major determinant of urinary connective tissue growth factor excretion.
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.
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. K.G.F.Gerritsen@umcutrecht.nl
Karin G
KG
Gerritsen
Hilde P
HP
Peters
Tri Q
TQ
Nguyen
Maarten P
MP
Koeners
Jack F
JF
Wetzels
Jaap A
JA
Joles
Erik I
EI
Christensen
Pierre J
PJ
Verroust
Dongxia
D
Li
Noelynn
N
Oliver
Leon
L
Xu
Robbert J
RJ
Kok
Roel
R
Goldschmeding
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D055513:Connective Tissue Growth Factor / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine*; D003430:Cross-Sectional Studies; D004705:Endocytosis; D005919:Glomerular Filtration Rate; D006801:Humans; D007263:Infusions, Parenteral; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine*; D011097:Polygeline / Q000008:administration & dosage; D051381:Rats; D011921:Rats, Inbred WKY; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000652:urine; D001613:beta 2-Microglobulin / Q000652:urine
D015415:Biomarkers; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin; C029486:intrinsic factor-cobalamin receptor; D055513:Connective Tissue Growth Factor; D011097:Polygeline