Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome
Open Access
- 1 March 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (3), 768-777
- https://doi.org/10.1172/jci39569
Abstract
The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization–associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3–/– mice, which model Alport syndrome. Ablation of Usag1 in Col4a3–/– mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3–/– mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.Keywords
This publication has 74 references indexed in Scilit:
- Transforming Growth Factor β-Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent GrowthMolecular and Cellular Biology, 2008
- Irradiation Prolongs Survival of Alport MiceJournal of the American Society of Nephrology, 2008
- Modulator of bone morphogenetic protein activity in the progression of kidney diseasesKidney International, 2006
- Role for Macrophage Metalloelastase in Glomerular Basement Membrane Damage Associated with Alport SyndromeThe American Journal of Pathology, 2006
- Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney diseaseProceedings of the National Academy of Sciences of the United States of America, 2006
- Stage-Specific Action of Matrix Metalloproteinases Influences Progressive Hereditary Kidney DiseasePLoS Medicine, 2006
- Role of macula densa neuronal nitric oxide synthase in renal diseasesMedical Molecular Morphology, 2006
- USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the kidneyBiochemical and Biophysical Research Communications, 2004
- Macula Densa Cell SignalingAnnual Review of Physiology, 2003
- Mutations in the type IV collagen α3 (COL4A3) gene in autosomal recessive Alport syndromeHuman Molecular Genetics, 1994