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-beta1 (TGF-beta1) 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-beta1 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.
Li
Can
C
Department of Internal Medicine and Anatomy, The Catholic University of Korea, Seoul, Korea.
Yang
Chul Woo
CW
Park
Cheol Whee
CW
Ahn
Hee Jong
HJ
Kim
Wan Young
WY
Yoon
Kun Ho
KH
Suh
Sun Hee
SH
Lim
Sun Woo
SW
Cha
Jung Ho
JH
Kim
Yong Soo
YS
Kim
Jin
J
Chang
Yoon Sik
YS
Bang
Byung Kee
BK
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000517:prevention & control; D004334:Drug Administration Schedule; D053331:Ectodysplasins; D007668:Kidney / Q000378:metabolism*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000473:pathology; D053495:Osteopontin; D012333:RNA, Messenger / Q000378:metabolism; D017257:Ramipril / Q000008:administration & dosage*; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D012795:Sialoglycoproteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000806:Angiotensin-Converting Enzyme Inhibitors; D053331:Ectodysplasins; D008565:Membrane Proteins; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D017257:Ramipril