ADAMTS1 induces renal inflammation and fibrosis via renin-angiotensin system

[Speaker] Hiroe Toba:1
[Co-author] Yusuke Watanabe:1, Naseratun Nessa:1, Takami Saito:1, Ryoki Kawashima:1, Shiho Sakaue:1, Miyuki Kobara:1, Tetsuo Nakata:1
1:Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Japan

Background: A disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), an enzyme involving extracellular matrix (ECM) turnover by degrading some particular ECM components, contributes to renal injury. ADAMTS1 is reported to play important roles in macrophage infiltration into atherosclerotic lesion and collagen deposition in the liver. This study was aimed to investigate the role of ADAMTS1 in renal injury and the contribution of renal renin-angiotensin system using deoxycorticosterone acetate (DOCA)-salt hypertensive rats.
Methods: DOCA (40 mg/kg/week, s.c.) and salt (1% in drinking water) are administered to uninephrectomized rats (n=5-6/group) for 0, 1, 2, or 3 weeks. Losartan (30mg/kg/day, p.o.) was administrated to DOCA-salt hypertensive rats for 3 weeks. We measured systolic blood pressure, proteinuria, plasma creatinine, and the activity of renal angiotensin converting enzyme (ACE) and NADPH oxidase. Sections were stained with Masson's trichrome staining. The protein levels of ADAMTS1, collagen I, TGF-beta, and osteopontin were examined by Western blotting.
Results: Blood pressure, proteinuria, plasma creatinine, and the activity of ACE and NADPH oxidase increased from 2 weeks. Fibrillar collagen deposition in tubulointerstitium and glomerulosclerosis increased time-dependently from 2 weeks. The collagen I protein, in particular collagen I with larger molecular weight (140kDa, 210kDa), increased in 3 weeks, while 70kDa Western bands showed no differences among groups, suggesting that post-translational collagen processing were stimulated in hypertensive rats. The expression of TGF-beta and osteopontin were upregulated in DOCA-salt rats. Both latent and active forms of ADAMTS1 increased in DOCA-salt groups from 1 week and 3 weeks, respectively. These increases in ADAMTS1 were attenuated by losartan treatment. Since secreted protein acidic and rich in cysteine (SPARC) is reported to promote collagen deposition via ADAMTS1 production, we measured SPARC expression and found that SPARC increased from 1 week and reversed to the control levels at 3 weeks.
Conclusions: ADAMTS1 may play important roles in progression of renal inflammation and fibrosis via renal renin-angiotensin system. Because SPARC is reported to be upregulated by angiotensin II, SPARC may mediate ADAMTS1 production in the hypertensive kidney.
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