Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.
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,...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2010
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| _version_ | 1797066587367276544 |
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| author | Tanaka, M Asada, M Higashi, A Nakamura, J Oguchi, A Tomita, M Yamada, S Asada, N Takase, M Okuda, T Kawachi, H Economides, A Robertson, E Takahashi, S Sakurai, T Goldschmeding, R Muso, E Fukatsu, A Kita, T Yanagita, M |
| author_facet | Tanaka, M Asada, M Higashi, A Nakamura, J Oguchi, A Tomita, M Yamada, S Asada, N Takase, M Okuda, T Kawachi, H Economides, A Robertson, E Takahashi, S Sakurai, T Goldschmeding, R Muso, E Fukatsu, A Kita, T Yanagita, M |
| author_sort | Tanaka, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T21:44:12Z |
| format | Journal article |
| id | oxford-uuid:48fe44d4-5285-49e6-96f0-9dd62b112436 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:44:12Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:48fe44d4-5285-49e6-96f0-9dd62b1124362022-03-26T15:29:00ZLoss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:48fe44d4-5285-49e6-96f0-9dd62b112436EnglishSymplectic Elements at Oxford2010Tanaka, MAsada, MHigashi, ANakamura, JOguchi, ATomita, MYamada, SAsada, NTakase, MOkuda, TKawachi, HEconomides, ARobertson, ETakahashi, SSakurai, TGoldschmeding, RMuso, EFukatsu, AKita, TYanagita, MThe 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. |
| spellingShingle | Tanaka, M Asada, M Higashi, A Nakamura, J Oguchi, A Tomita, M Yamada, S Asada, N Takase, M Okuda, T Kawachi, H Economides, A Robertson, E Takahashi, S Sakurai, T Goldschmeding, R Muso, E Fukatsu, A Kita, T Yanagita, M Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. |
| title | Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. |
| title_full | Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. |
| title_fullStr | Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. |
| title_full_unstemmed | Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. |
| title_short | Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. |
| title_sort | loss of the bmp antagonist usag 1 ameliorates disease in a mouse model of the progressive hereditary kidney disease alport syndrome |
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