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Journal of Diabetes Research
Volume 2015, Article ID 539787, 11 pages
Research Article

Elevated Urinary Connective Tissue Growth Factor in Diabetic Nephropathy Is Caused by Local Production and Tubular Dysfunction

1Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands
2Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands
3Department of Internal Medicine, University Medical Center Groningen, 9700 RB Groningen, Netherlands
4HaemoScan, 9723 JC Groningen, Netherlands
5Department of Pathology, Academic Medical Center, 1105 AZ Amsterdam, Netherlands
6Steno Diabetes Center, 2820 Gentofte, Denmark
7Department of Nephrology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, Netherlands
8Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, Netherlands

Received 17 February 2015; Revised 27 May 2015; Accepted 3 June 2015

Academic Editor: Amandine Gautier-Stein

Copyright © 2015 Karin G. F. Gerritsen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.