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 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.

Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis

“…30,49,50 Primary antibodies against the following proteins were used for immunostaining: hHBegf (R&D Systems), aquaporin 1 (Abcam, Inc., Cambridge, MA), Tamm …”

“…50 Specific primers were designed using Primer Express software (Applied Biosystems, Foster City, CA). Serially diluted cDNA was used to generate the standard curves for each primer.…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…The Sostdc1 knockout allele was generated by replacing both Sostdc1 exons with an in-frame LacZ reporter [177]. LacZ stains were performed on fixed tissues (fractured and intact femora at days 3, 7, 10, 14, and 21 post-fracture, n=3 per group, per time point, male mice) of Sostdc1 +/-and Sostdc1 -/-mice as previously described [187] with minor modifications.…”

“…Sostdc1, a paralog of Sost also known by several other names including SostLike, Wise, Ectodin and Usag-1 arose by segmental gene duplication and was previously studied in the context of tooth development, kidney disease, cancer progression, hair follicle formation, and embryo implantation [103,[177][178][179][180][181]. Recently, we have shown that Sostdc1 also contributes to limb morphogenesis [104], and its expression in the periosteum suggests that it may also play a role in bone maintenance and repair.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…Such extracellular BMP signaling inhibitors include noggin, 114 gremlin, 115 CRIM1, 116 DAN/cerberus, 117 vertebrate chordin 118 and uterine sensitization-associated gene-1 (USAG-1). 119 In contrast, Kielin/chordin-like protein (KCP) protein is an extracellular protein that enhances the activity of BMP7 by amplifying the physical interaction of BMP7 with its receptor. 120 BMP7 is a member of the TGF-b superfamily.…”