Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.

Journal article

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.

Authors: Tanaka, M; Asada, M; Higashi, A; Nakamura, J; Oguchi, A

• Publication status: Published
• Journal: Journal of clinical investigation
• Volume: 120
• Issue: 3
• Pages: 768-777
• Publication date: 2010-03-01
• DOI: 10.1172/jci39569
• EISSN: 1558-8238
• ISSN: 0021-9738
• Language: English
• Keywords: Bone Morphogenetic Protein 7; Acute Kidney Injury; Disease Models, Animal; Kidney Tubules; Glomerular Basement Membrane; Nephritis, Hereditary; Collagen Type IV; Glomerular Mesangium; Mice, Knockout; Mutation; Animals; Humans; Bone Morphogenetic Proteins; Mice