TY - JOUR
T1 - Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury
AU - Yanagita, Motoko
AU - Okuda, Tomohiko
AU - Endo, Shuichiro
AU - Tanaka, Mari
AU - Takahashi, Katsu
AU - Sugiyama, Fumihiro
AU - Kunita, Satoshi
AU - Takahashi, Satoru
AU - Fukatsu, Atsushi
AU - Yanagisawa, Masashi
AU - Kita, Toru
AU - Sakurai, Takeshi
PY - 2006/1
Y1 - 2006/1
N2 - Dialysis dependency is one of the leading causes of morbidity and mortality in the world, and once endstage 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.
AB - Dialysis dependency is one of the leading causes of morbidity and mortality in the world, and once endstage 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.
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U2 - 10.1172/JCI25445
DO - 10.1172/JCI25445
M3 - Article
C2 - 16341262
AN - SCOPUS:31044453402
SN - 0021-9738
VL - 116
SP - 70
EP - 79
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -