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

• Published in: The Journal of clinical investigation Vol. 120; no. 3; pp. 768 - 777
• Main Authors: Tanaka, Mari, Asada, Misako, Higashi, Atsuko Y, Nakamura, Jin, Oguchi, Akiko, Tomita, Mayumi, Yamada, Sachiko, Asada, Nariaki, Takase, Masayuki, Okuda, Tomohiko, Kawachi, Hiroshi, Economides, Aris N, Robertson, Elizabeth, Takahashi, Satoru, Sakurai, Takeshi, Goldschmeding, Roel, Muso, Eri, Fukatsu, Atsushi, Kita, Toru, Yanagita, Motoko
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.03.2010
• Subjects: Alport's syndrome; Animal models in research; Bone morphogenetic proteins; Genetic aspects; Physiological aspects; Risk factors; Japan
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI39569.

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.sup.[-/-]] mice, which model Alport syndrome. Ablation of Usag1 in [Col4a3.sup.[-/-]]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.sup.[-/-]] 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.