title: 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.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Tanaka
authors.forename: Misako
authors.initials: M
authors.lastname: Asada
authors.forename: Atsuko Y
authors.initials: AY
authors.lastname: Higashi
authors.forename: Jin
authors.initials: J
authors.lastname: Nakamura
authors.forename: Akiko
authors.initials: A
authors.lastname: Oguchi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tomita
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Nariaki
authors.initials: N
authors.lastname: Asada
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takase
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Robertson
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Eri
authors.initials: E
authors.lastname: Muso
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukatsu
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D050533:Glomerular Basement Membrane / Q000378:metabolism* / Q000473:pathology; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D024141:Collagen Type IV; C483887:Sostdc1 protein, mouse