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Relaxin increases ubiquitin-dependent degradation of fibronectin in vitro and ameliorates renal fibrosis in vivo

¹Division of Renal Diseases and Hypertension, The University of Texas Medical School at Houston, Houston, Texas 77030; ²Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston 02215; ³Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and ⁴Connetics Corporation, Palo Alto, California 94303

Submitted 23 April 2002 ; accepted in final form 4 March 2003

Fibronectin, a large adhesive glycoprotein, is a prominent constituent of the extracellular matrix. Abnormalities in fibronectin homeostasis occur in numerous disease states, ranging from primary fibrosing conditions to neoplastic transformation. We demonstrate that fibronectin is a target protein substrate for ubiquitin-dependent degradation. Coimmunoprecipitation experiments and confocal microscopy demonstrated ubiquitin-fibronectin interaction. In an in vitro model of renal fibrosis, relaxin, an insulin-like growth factor, increased ubiquitin-dependent fibronectin degradation. Relaxin also was evaluated in an anti-glomerular basement membrane model of renal fibrosis. Animals treated with relaxin experienced renoprotection, manifested by decreased serum creatinine and proteinuria. Histological evaluation of kidney sections from animals treated with relaxin showed decreased glomerulosclerosis and interstitial fibrosis. We conclude that relaxin might be developed as a useful agent for the treatment of renal fibrosis.

fibrosis; protein degradation; kidney

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