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

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.

• Authors: Mari Tanaka, Misako Asada, Atsuko Y Higashi, Jin Nakamura, Akiko Oguchi, Mayumi Tomita, Sachiko Yamada, Nariaki Asada, Masayuki Takase, Tomohiko Okuda, Hiroshi Kawachi, Aris N Economides, Elizabeth Robertson, Satoru Takahashi, Takeshi Sakurai, Roel Goldschmeding, Eri Muso, Atsushi Fukatsu, Toru Kita, Motoko Yanagita
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 3 Pg. 768-77 (Mar 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 20197625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Bone Morphogenetic Protein 7
• Bone Morphogenetic Proteins
• Collagen Type IV
• Sostdc1 protein, mouse

Topics

• Acute Kidney Injury (genetics, metabolism, pathology)
• Adaptor Proteins, Signal Transducing
• Animals
• Bone Morphogenetic Protein 7 (antagonists & inhibitors, genetics, metabolism)
• Bone Morphogenetic Proteins (genetics, metabolism)
• Collagen Type IV (genetics, metabolism)
• Disease Models, Animal
• Glomerular Basement Membrane (metabolism, pathology)
• Glomerular Mesangium (metabolism, pathology)
• Humans
• Kidney Tubules (metabolism, pathology)
• Mice
• Mice, Knockout
• Mutation
• Nephritis, Hereditary (genetics, metabolism, pathology)