The Journal of clinical investigation, 2010-03, Vol.120 (3), p.768-777
2010
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- Autor(en) / Beteiligte
- Titel
- Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome
- Ist Teil von
- The Journal of clinical investigation, 2010-03, Vol.120 (3), p.768-777
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/jci39569Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2827946
- Format
- –
- Schlagworte
- Ablation, Acute Kidney Injury - genetics, Acute Kidney Injury - metabolism, Acute Kidney Injury - pathology, Age, Alport's syndrome, Animal models in research, Animals, Biomedical research, Bone Morphogenetic Protein 7 - antagonists & inhibitors, Bone Morphogenetic Protein 7 - genetics, Bone Morphogenetic Protein 7 - metabolism, Bone morphogenetic proteins, Bone Morphogenetic Proteins - genetics, Bone Morphogenetic Proteins - metabolism, Collagen, Collagen Type IV - genetics, Collagen Type IV - metabolism, Creatinine, Disease Models, Animal, Genes, Genetic aspects, Glomerular Basement Membrane - metabolism, Glomerular Basement Membrane - pathology, Glomerular Mesangium - metabolism, Glomerular Mesangium - pathology, Humans, Kidney diseases, Kidney Tubules - metabolism, Kidney Tubules - pathology, Mice, Mice, Knockout, Mutation, Nephritis, Hereditary - genetics, Nephritis, Hereditary - metabolism, Nephritis, Hereditary - pathology, Physiological aspects, Proteins, Risk factors