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, 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.
Tanaka
Mari
M
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Asada
Misako
M
Higashi
Atsuko Y
AY
Nakamura
Jin
J
Oguchi
Akiko
A
Tomita
Mayumi
M
Yamada
Sachiko
S
Asada
Nariaki
N
Takase
Masayuki
M
Okuda
Tomohiko
T
Kawachi
Hiroshi
H
Economides
Aris N
AN
Robertson
Elizabeth
E
Takahashi
Satoru
S
Sakurai
Takeshi
T
Goldschmeding
Roel
R
Muso
Eri
E
Fukatsu
Atsushi
A
Kita
Toru
T
Yanagita
Motoko
M
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
D048868:Adaptor Proteins, Signal Transducing; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D024141:Collagen Type IV; C483887:Sostdc1 protein, mouse