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[PP.02.11] A DISINTEGRIN AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF (ADAMTS1) CAUSES RENAL FIBROSIS IN DEOXYCORTICOSTERONE ACETATE-SALT HYPERTENSIVE RATS

Objective: The extracellular matrix (ECM) not only provides structural support in many tissues but also plays important biological roles. ECM accumulation and/or imbalance of ECM components implicate various pathological states such as excessive fibrosis. A disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) have been indicated to facilitate collagen deposition via transforming growth factor-&bgr; (TGF-&bgr;) activation in some tissues. This study investigated the role of ADAMTS1 in renal fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Design and method: Uninephrectomized rats were treated with DOCA (40 mg/kg/week, s.c.) and 1% NaCl (in drinking water) for 0, 1, 2, or 3 weeks (n = 5–6/group). Blood pressure, urinary protein excretion, and plasma creatinine were measured. Renal sections were stained with Masson's trichrome to detect collagen fibers. The protein expression of collagen I, TGF-&bgr;, and ADAMTS1 was examined by Western blotting. The angiotensin converting enzyme (ACE) activity was also measured. Results: Blood pressure showed time-dependent increases from 2 weeks, and the levels of proteinuria and plasma creatinine increased from 2 weeks. Masson's trichrome-positive collagen content increased from 2 weeks with an additional increase in 3 weeks. On the other hand, Western blot analysis demonstrated that the collagen I protein levels equally increased in 1-, 2-, and 3-week groups, indicating that the blood pressure elevation may accelerate post-translational collagen processing but not collagen I production. The expression of ADAMTS1 (both 110kDa latent and 87kDa active forms) as well as that of TGF-&bgr; increased in 2 and 3 weeks, suggesting a potential role of ADAMTS1 as an inducer of collagen processing and deposition. The ACE activity was enhanced in 2 and 3 weeks. Since the renin-angiotensin system is reported to increase ADAMTS1 expression, the activation of ACE might relate to ADAMTS1 upregulation in DOCA-salt rat kidney. Conclusions: ADAMTS1, which is reported to induce fibrosis in other tissues, may be an important inducer of renal fibrosis in hypertensive rats. Further investigation to show that ADAMTS1 production and activation are placed in the upstream of collagen accumulation and downstream of ACE will strengthen our hypothesis.