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.
Yanagita
Motoko
M
Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. motoy@kuhp.kyoto-u.ac.jp
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C480733:SOSTDC1 protein, human; C483887:Sostdc1 protein, mouse; D016212:Transforming Growth Factor beta