Hormones – Cytokines – Signaling
Kidney International (2003) 63, 454–463; doi:10.1046/j.1523-1755.2003.00751.x
Long-term treatment with ramipril attenuates renal osteopontin expression in diabetic rats
Can Li, Chul Woo Yang, Cheol Whee Park, Hee Jong Ahn, Wan Young Kim, Kun Ho Yoon, Sun Hee Suh, Sun Woo Lim, Jung Ho Cha, Yong Soo Kim, Jin Kim, Yoon Sik Chang and Byung Kee Bang
Departments of Internal Medicine and Anatomy, The Catholic University of Korea, Seoul, Korea, and Nephrology and Dialysis Unit, Department of Internal Medicine, Affiliated Hospital, YanBian University Medical College, JiLin, People's Republic of China
Correspondence: Byung Kee Bang, M.D., PhD., Department of Internal Medicine, KangNam St. Mary's Hospital, The Catholic University of Korea, 505 BanPo-Dong, SeoCho-Ku, Seoul, 137-040, Korea. E-mail: nephron@catholic.ac.kr
Received 6 November 2001; Revised 23 July 2002; Accepted 10 September 2002.
Abstract
Long-term treatment with ramipril attenuates renal osteopontin expression in diabetic rats.
Background
Osteopontin (OPN) mediates progressive renal injury in various renal diseases by attracting macrophages, and its expression is regulated by the renin-angiotensin system (RAS). We studied the association between OPN expression and tubulointerstitial injury, and investigated the effect of ramipril on OPN expression in an animal model of non–insulin-dependent diabetes mellitus (NIDDM): Otsuka Long-Evans Tokushima Fatty (OLETF) rats.
Methods
Control (Long-Evans Tokushima Otsuka, LETO) and diabetic (OLETF) rats were treated with ramipril (3 mg/kg in drinking water) or vehicle for nine months, starting at 20 weeks of age. Systolic blood pressure, body weight, urinary protein excretion and oral glucose tolerance tests (OGTT) were monitored periodically. Renal function, histology (glomerulosclerosis, tubulointerstitial fibrosis, and ED-1-positive cells as a measure of macrophage infiltration), and expressions of OPN and transforming growth factor-
1 (TGF-1) were evaluated at the end of the study.
Results
Compared with the LETO rats, OLETF rats showed declines in creatinine clearance rate, increases in urinary protein excretion and systolic blood pressure, and development of glomerulosclerosis, tubulointerstitial fibrosis, and inflammatory cell infiltration (all P < 0.05). Blocking angiotensin II with ramipril significantly improved all of these parameters (all P < 0.01). At the molecular level, expressions of OPN and TGF-1 were up-regulated in the OLETF rats, and were markedly suppressed following ramipril treatment. The sites of strong OPN mRNA and protein expressions were localized to areas of renal injury. Of note, the expression of OPN mRNA was strongly correlated with the number of ED-1-positive cells (r = 0.560, P = 0.01) and the tubulointerstitial fibrosis score (r = 0.500, P < 0.05).
Conclusions
Up-regulation of OPN expression may play a role in tubulointerstitial injury associated with diabetic nephropathy, and blockade of the RAS by ramipril may confer renoprotection by decreasing OPN expression in non–insulin-dependent diabetic nephropathy.
Keywords:
osteopontin, macrophage, ramipril, tubulointerstitial injury, OLETF, renin-angiotensin system, TGF-, renoprotection
