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

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

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Figure 2

Usag1–/–Col4a3–/– mice showed less albuminuria and preserved renal function.

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Usag1–/–Col4a3–/– mice showed less albuminuria and preserved renal func...
(A) Urinary albumin excretion normalized by urinary creatinine in WT littermates (WT/WT, n = 4), Usag1+/+Col4a3–/– mice (WT/KO, n = 8), Usag1+/–Col4a3–/– mice (HE/KO, n = 5), and Usag1–/–Col4a3–/– mice (KO/KO, n = 7) at 6 weeks of age. Open circles represent mean value of each column, while closed circles represent individual mice. (B) Plasma creatinine and blood urea nitrogen (BUN) levels in WT littermates (WT/WT, n = 20), Usag1+/+Col4a3–/– mice (WT/KO, n = 18), Usag1+/–Col4a3–/– mice (HE/KO, n = 34), and Usag1–/–Col4a3–/– mice (KO/KO, n = 17) at 10 weeks of age. Bars indicate mean ± SD. Open circles represent mean value of each column, while closed circles represent individual mice.