CTGF Inhibits BMP-7 Signaling in Diabetic Nephropathy

Nguyen TQ; Roestenberg P; van Nieuwenhoven FA; Bovenschen N; Li Z.; Xu, L; Oliver N.; Aten J; Joles JA; Vial, C; Brandan, E.; Lyons KM; Goldschmeding, R

Abstract

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. Copyright © 2008 by the American Society of Nephrology.

Más información

Título según WOS: CTGF Inhibits BMP-7 Signaling in Diabetic Nephropathy
Título según SCOPUS: CTGF inhibits BMP-7 signaling in diabetic nephropathy
Título de la Revista: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volumen: 19
Número: 11
Editorial: AMER SOC NEPHROLOGY
Fecha de publicación: 2008
Página de inicio: 2098
Página final: 2107
Idioma: English
URL: http://www.jasn.org/cgi/doi/10.1681/ASN.2007111261
DOI:

10.1681/ASN.2007111261

Notas: ISI, SCOPUS