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CTGF Inhibits BMP-7 Signaling in Diabetic Nephropathy

Tri Q. Nguyen^*, Peggy Roestenberg^*, Frans A. van Nieuwenhoven^*, Niels Bovenschen^*, Zeke Li, Leon Xu, Noelynn Oliver, Jan Aten, Jaap A. Joles, Cecilia Vial^||, Enrique Brandan^||, Karen M. Lyons^¶ and Roel Goldschmeding^*

Departments of ^* Pathology and Nephrology, University Medical Center Utrecht, Utrecht, and Department of Pathology, Academic Medical Center, Amsterdam, Netherlands; FibroGen, Inc., South San Francisco, and ^¶ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California; and ^|| Department of Cell and Molecular Biology, Catholic University of Chile, Santiago, Chile

Correspondence: Dr. Roel Goldschmeding, University Medical Center Utrecht, Department of Pathology, H04.312, Heidelberglaan 100, 3584 CX, Utrecht, Netherlands. Phone: +31-88-755-6559; Fax: +31-30-254-4990; E-mail: R.Goldschmeding{at}umcutrecht.nl

Received for publication November 29, 2007. Accepted for publication May 21, 2008.

In diabetic nephropathy, connective tissue growth factor (CTGF) is upregulated and bone morphogenetic protein 7 (BMP-7) is downregulated. CTGF is known to inhibit BMP-4, but similar cross-talk between BMP-7 and CTGF has not been studied. In this study, it was hypothesized that CTGF acts as an inhibitor of BMP-7 signaling activity in diabetic nephropathy. Compared with diabetic wild-type CTGF^+/+ mice, diabetic CTGF^+/– mice had approximately 50% lower CTGF mRNA and protein, less severe albuminuria, no thickening of the glomerular basement membrane, and preserved matrix metalloproteinase (MMP) activity. Although the amount of BMP-7 mRNA was similar in the kidneys of diabetic CTGF^+/+ and CTGF^+/– mice, phosphorylation of the BMP signal transduction protein Smad1/5 and expression of the BMP target gene Id1 were lower in diabetic CTGF^+/+ mice. Moreover, renal Id1 mRNA expression correlated with albuminuria (R = –0.86) and MMP activity (R = 0.76). In normoglycemic mice, intraperitoneal injection of CTGF led to a decrease of pSmad1/5 in the renal cortex. In cultured renal glomerular and tubulointerstitial cells, CTGF diminished BMP-7 signaling activity, evidenced by lower levels of pSmad1/5, Id1 mRNA, and BMP-responsive element–luciferase activity. Co-immunoprecipitation, solid-phase binding assay, and surface plasmon resonance analysis showed that CTGF binds BMP-7 with high affinity (Kd approximately 14 nM). In conclusion, upregulation of CTGF inhibits BMP-7 signal transduction in the diabetic kidney and contributes to altered gene transcription, reduced MMP activity, glomerular basement membrane thickening, and albuminuria, all of which are hallmarks of diabetic nephropathy.

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