Balance between bone morphogenetic proteins and their antagonists in kidney injury.

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 the administration of large dose of bone morphogenetic protein-7 (BMP-7) has been shown to repair established renal injuries and improves renal function, pathophysiological role of endogenous BMP-7 and regulatory mechanism of its activities remain elusive. Here we show that uterine sensitization-associated gene-1 (USAG-1), 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 (USAG-1(-/-) mice) are resistant to kidney injuries. USAG-1(-/-) mice exhibited prolonged survival and preserved renal function in acute and chronic renal injuries. Renal BMP signaling, assessed by phosphorylation of Smad proteins, is significantly enhanced in USAG-1(-/-) mice during renal injury, indicating that the preservation of renal function is attributed to enhancement of endogenous BMP signaling. Furthermore, the administration of neutralizing antibody against BMP-7 abolished reno-protection in USAG-1(-/-) mice, indicating that USAG-1 plays a critical role in the modulation of reno-protective action of BMP, and that inhibition of USAG-1 will be promising means of development of novel treatment for kidney diseases.