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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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 2

USAG1–/– mice showed less renal injury in cisplatin nephrotoxicity.

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USAG1–/– mice showed less renal injury in cisplatin nephrotoxicity. ...
(A) Survival curves of wild-type mice (black line) and USAG1–/– mice (red line) after cisplatin administration (n = 24). (B) Serum creatinine (Cre) and blood urea nitrogen (BUN) levels at 3 days after injection of cisplatin (n = 6). (C) Representative renal histological findings in wild-type mice and USAG1–/– mice on day 3. Scale bars: 100 μm. (D) Semiquantitative evaluation of morphologic kidney damage, expressed as relative severity on a scale from 0 to 4 (n = 6). Morphological findings were scored according to proximal tubule brush border loss (BB loss), tubule dilatation (Dilatation), tubule degeneration (Degeneration), and tubule necrosis (Necrosis). *P < 0.01; **P < 0.001. (E) E-cadherin expression in cisplatin nephrotoxicity. Kidney lysates were subjected to immunoblotting with anti–E-cadherin antibody. Representative data from 4 independent experiments are shown. (F) TUNEL staining of kidneys on day 3 of cisplatin nephrotoxicity. The number of TUNEL-positive cells per section was counted in transverse sections (n = 6). Scale bars: 10 μm. (G) Gene expression in cisplatin nephrotoxicity. Gene expression was determined by real-time RT-PCR. In each experiment, expression levels were normalized to the expression of GAPDH and expressed relative to mice on day 0. n = 4–6 for each experiment. †P < 0.005; #P < 0.02. Col4α1, collagen type IV α 1. (H) Infiltration of Mac-1–positive cells after cisplatin injection. The number of Mac-1–positive cells per field was counted in 10 consecutive fields (n = 6). Scale bars: 100 μm.