CTGF Inhibits BMP-7 Signaling in Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology 2008-11, Vol.19 (11), p.2098-2107
• Main Authors: NGUYEN, Tri Q, ROESTENBERG, Peggy, BRANDAN, Enrique, LYONS, Karen M, GOLDSCHMEDING, Roel, VAN NIEUWENHOVEN, Frans A, BOVENSCHEN, Niels, ZEKE LI, XU, Leon, OLIVER, Noelynn, ATEN, Jan, JOLES, Jaap A, VIAL, Cecilia
• Format: Article
• Language: English
• Subjects: Animals; Associated diseases and complications; Basic Research; Biological and medical sciences; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins - deficiency; Bone Morphogenetic Proteins - genetics; Bone Morphogenetic Proteins - physiology; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - genetics; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Gene Expression; Immediate-Early Proteins - deficiency; Immediate-Early Proteins - genetics; Immediate-Early Proteins - pharmacology; Immediate-Early Proteins - physiology; Inhibitor of Differentiation Protein 1 - genetics; Intercellular Signaling Peptides and Proteins - deficiency; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - pharmacology; Intercellular Signaling Peptides and Proteins - physiology; Kidney - metabolism; Kidney - pathology; Kidneys; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nephrology. Urinary tract diseases; Protein Binding; Recombinant Proteins - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Smad1 Protein - metabolism; Smad5 Protein - metabolism; Transforming Growth Factor beta - deficiency; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - physiology; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2007111261

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.