title: CTGF inhibits BMP-7 signaling in diabetic nephropathy.
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.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, H04.312, Heidelberglaan 100, 3584 CX, Utrecht, Netherlands.
authors.forename: Tri Q
authors.initials: TQ
authors.lastname: Nguyen
authors.forename: Peggy
authors.initials: P
authors.lastname: Roestenberg
authors.forename: Frans A
authors.initials: FA
authors.lastname: van Nieuwenhoven
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
authors.forename: Zeke
authors.initials: Z
authors.lastname: Li
authors.forename: Leon
authors.initials: L
authors.lastname: Xu
authors.forename: Noelynn
authors.initials: N
authors.lastname: Oliver
authors.forename: Jan
authors.initials: J
authors.lastname: Aten
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.forename: Cecilia
authors.initials: C
authors.lastname: Vial
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lyons
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C526318:CCN2 protein, mouse; C497455:Idb1 protein, mouse; D017874:Immediate-Early Proteins; D051798:Inhibitor of Differentiation Protein 1; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor