OSTEONECTIN AND A DISINTEGRIN AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF (ADAMTS1) INDUCE FIBROSIS IN DEOXYCORTICOSTERONE-SALT HYPERTENSIVE RAT KIDNEY. (June 2018) - Toba, H.
Abstract : Objective: Osteonectin (secreted protein acidic and rich in cysteine:SPARC) and a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), both of which regulate various cell function in development and tissue formation, promote collagen deposition in some tissues. We reported a positive correlation between ADAMTS1 and fibrillar collagen deposition in deoxycorticosterone acetate (DOCA)-salt hypertensive rats (ESH2017). This study investigated; 1) the roles of osteonectin and ADAMTS1 in renal fibrosis, and 2) the contribution of renin-angiotensin system in the regulation of osteonectin and ADAMTS1 in DOCA-salt hypertensive rats. Design and method: Uninephrectomized rats (n = 5-6/group) were treated with DOCA (40 mg/kg/week, s.c.) and 1% NaCl (in drinking water) for 0, 1, 2, or 3 weeks with/without losartan (30 mg/kg/day, p.o.). Blood pressure, proteinuria, and plasma creatinine levels were measured. Fibrillar collagens were detected by Masson's trichrome staining. The protein levels of osteopontin, collagen I, TGF-β, osteonectin, ADAMTS1, and angiotensin converting enzyme (ACE) were examined by Western blotting. We also measured the ACE and NADPH oxidase activity. Results: Blood pressure showed time-dependent increases from 2 weeks, and the levels of proteinuria and plasma creatinine increased from 2 weeks. Fibrillar collagen deposition occurred from 2 weeks with an additional increase in 3 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, not production, were stimulated in hypertensive rats. The expression of osteopontin, TGF-β, and ACE and the activity of ACE and NADPH oxidase were upregulated in accordance with blood pressure elevation. Latent ADAMTS1 increased in 1 week, and active forms increased in 3 weeks, which were decreased by losartan treatment. Osteonectin levels elevated from 1 week and reversed to the control levels at 3 weeks. Conclusions: Osteonectin (SPARC) may induce renal inflammation and fibrosis through ADAMTS1 upregulation in hypertensive rats. Further investigation to show that osteonectin and subsequent ADAMTS1 upregulation is placed in the upstream of fibrosis and downstream of renin-angiotensin system will be needed.