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

腎不全治療の新しい可能性の発見－腎不全をきたす遺伝病、アルポート症候群はBMP阻害分子USAG-1欠損によって軽快し、腎不全に陥らない－. 京都大学プレスリリース. 2010-02-09. http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2009/100209_1.htmThe 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 causeAlport 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 thedistal 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 toGBM 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 promisingtherapeutic approach for the treatment of Alport syndrome.