title: Elevated Urinary Connective Tissue Growth Factor in Diabetic Nephropathy Is Caused by Local Production and Tubular Dysfunction.
abstract: Connective tissue growth factor (CTGF; CCN2) plays a role in the development of diabetic nephropathy (DN). Urinary CTGF (uCTGF) is elevated in DN patients and has been proposed as a biomarker for disease progression, but it is unknown which pathophysiological factors contribute to elevated uCTGF. We studied renal handling of CTGF by infusion of recombinant CTGF in diabetic mice. In addition, uCTGF was measured in type 1 DN patients and compared with glomerular and tubular dysfunction and damage markers. In diabetic mice, uCTGF was increased and fractional excretion (FE) of recombinant CTGF was substantially elevated indicating reduced tubular reabsorption. FE of recombinant CTGF correlated with excretion of endogenous CTGF. CTGF mRNA was mainly localized in glomeruli and medullary tubules. Comparison of FE of endogenous and recombinant CTGF indicated that 60% of uCTGF had a direct renal source, while 40% originated from plasma CTGF. In DN patients, uCTGF was independently associated with markers of proximal and distal tubular dysfunction and damage. In conclusion, uCTGF in DN is elevated as a result of both increased local production and reduced reabsorption due to tubular dysfunction. We submit that uCTGF is a biomarker reflecting both glomerular and tubulointerstitial hallmarks of diabetic kidney disease.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands ; Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Karin G F
authors.initials: KG
authors.lastname: Gerritsen
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Leeuwis
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: Koeners
authors.affiliation: Department of Internal Medicine, University Medical Center Groningen, 9700 RB Groningen, Netherlands.
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.affiliation: HaemoScan, 9723 JC Groningen, Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: van Oeveren
authors.affiliation: Department of Pathology, Academic Medical Center, 1105 AZ Amsterdam, Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Aten
authors.affiliation: Steno Diabetes Center, 2820 Gentofte, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Steno Diabetes Center, 2820 Gentofte, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Department of Nephrology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, Netherlands.
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, Netherlands.
authors.forename: Robbert Jan
authors.initials: RJ
authors.lastname: Kok
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000652:urine; D015331:Cohort Studies; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism / Q000652:urine*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000652:urine*; D005260:Female; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007686:Kidney Tubules, Distal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000652:urine; D065667:Renal Elimination; D065608:Renal Reabsorption; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; D055513:Connective Tissue Growth Factor