Uterine sensitization-associated gene–1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury
Motoko Yanagita, … , Toru Kita, Takeshi Sakurai
Motoko Yanagita, … , Toru Kita, Takeshi Sakurai
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):70-79. https://doi.org/10.1172/JCI25445.
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Research Article Nephrology

Uterine sensitization-associated gene–1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury

Abstract

Dialysis dependency is one of the leading causes of morbidity and mortality in the world, and once end-stage renal disease develops, it cannot be reversed by currently available therapy. Although administration of large doses of bone morphogenetic protein–7 (BMP-7) has been shown to repair established renal injury and improve renal function, the pathophysiological role of endogenous BMP-7 and regulatory mechanism of its activities remain elusive. Here we show that the product of uterine sensitization-associated gene–1 (USAG1), a novel BMP antagonist abundantly expressed in the kidney, is the central negative regulator of BMP function in the kidney and that mice lacking USAG-1 (USAG1–/– mice) are resistant to renal injury. USAG1–/– mice exhibited prolonged survival and preserved renal function in acute and chronic renal injury models. Renal BMP signaling, assessed by phosphorylation of Smad proteins, was significantly enhanced in USAG1–/– mice with renal injury, indicating that the preservation of renal function is attributable to enhancement of endogenous BMP signaling. Furthermore, the administration of neutralizing antibody against BMP-7 abolished renoprotection in USAG1–/– mice, indicating that USAG-1 plays a critical role in the modulation of renoprotective action of BMP and that inhibition of USAG-1 is a promising means of development of novel treatment for renal diseases.

Authors

Motoko Yanagita, Tomohiko Okuda, Shuichiro Endo, Mari Tanaka, Katsu Takahashi, Fumihiro Sugiyama, Satoshi Kunita, Satoru Takahashi, Atsushi Fukatsu, Masashi Yanagisawa, Toru Kita, Takeshi Sakurai

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Figure 1

Generation of USAG1–/– mutation by gene targeting.

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Generation of USAG1–/– mutation by gene targeting. (A) U...
(A) USAG1–null allele was generated by homologous recombination in ES cells. Exon 1 (black box) and part of the intron were replaced with a lacZ gene (white box) and the NeoR cassette (gray box). (B) Analysis of USAG1+/+ (WT) and correctly targeted heterozygous (Hetero) ES cell clones by Southern blot analysis using 5′ genomic probe (thick black line in A). (C) PCR genotyping of F2 littermates. Template(–) is the negative control. (D) Northern blot analysis of USAG1 mRNA in the kidney of USAG1+/+ and USAG1–/– (KO) mice.