PubMed · 14630457
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Bengt Hj Möller. 2003-11-15. The CHARM programme.. https://doi.org/10.1016/s0140-6736(03)14812-x
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OBJECTIVES: In addition to its vasoactive effects, angiotensin II has proinflammatory properties. Angiotensin-converting enzyme (ACE) inhibitors reduce the production of angiotensin II and could therefore act as anti-inflammatory agents. Here we investigated the capacity of the ACE inhibitor quinapril to modulate inflammatory arthritis. METHODS: We studied the effect of quinapril on disease activity in mice with collagen-induced arthritis (CIA). Mice received oral quinapril (10 mg/kg/day) at the time of arthritis induction (prophylaxis protocol) or at the onset of mild arthritis (therapy protocol). Concentrations of immunoglobulin G (IgG) subtypes specific for bovine Type II collagen and TNF-alpha were measured by enzyme-linked immunoassay. RESULTS: Quinapril significantly diminished the activity of CIA when given as prophylaxis or therapy (prophylaxis protocol, P<0.001; therapy protocol P=0.002). Antigen-specific IgG2a antibodies were reduced by 52% (P=0.02) in the quinapril prophylaxis protocol. Suppression of arthritis by quinapril was associated with reduced articular expression of TNF-alpha by 68% (P=0.01) in the prophylaxis protocol and 27% (P=0.06) in the therapy protocol. Quinapril therapy also inhibited expression of splenocyte TNF-alpha production following lipopolysaccharide (LPS) in vitro stimulation by 59% (P=0.02). In parallel human in vitro experiments, ACE inhibition suppressed LPS-stimulated production of TNF-alpha by monocytes. In order to confirm that the action of quinapril occurred predominantly through suppression of angiotensin II, parallel experiments with the angiotensin receptor antagonist candesartan cilexetil demonstrated that this agent also inhibited disease activity in CIA. CONCLUSIONS: These data suggest that angiotensin II is a mediator of chronic inflammation and that ACE inhibition may have therapeutic effects in human inflammatory arthritis.
BACKGROUND/AIMS: Increased oxidative stress is involved in the aetiology of diabetic nephropathy, and angiotensin II is reported to play a considerable role in the development of renal damage in diabetic kidney. Angiotensin antagonism can slow the progression of renal impairment in diabetes. The present study was thus designed to examine the effect of an angiotensin II type 1 (AT1) receptor antagonist, irbesartan on renal function, oxidative stress and nitric oxide (NO) release in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetes was induced by a single intraperitoneal injection of streptozotocin (65 mg/kg) in rats. After 4 weeks of STZ injection, rats were divided into four groups: the control rats, diabetic rats and diabetic rats treated with irbesartan (25 and 50 mg/kg, orally) respectively till 8 weeks starting from 4 weeks after STZ injection. Renal function was assessed by creatinine, blood urea nitrogen, creatinine clearance and urea clearance. Oxidative stress was measured by renal malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase. We also measured renal nitrite levels. RESULTS: At the end of the 8th week, diabetic rats exhibited renal dysfunction as evidenced by reduced creatinine and urea clearance along with enhanced albumin excretion rate as compared with control rats. Biochemical analysis of kidneys revealed a marked increase in oxidative stress demonstrated by increased lipid peroxidation and decreased activities of key antioxidant enzymes, GSH, SOD and catalase in diabetic rats. NO release was also significantly higher in diabetic rats than controls. Chronic treatment with irbesartan in diabetic rats significantly attenuated both renal dysfunction and oxidative stress along with increased NO levels as compared with untreated diabetic rats. The kidneys of diabetic rats showed morphological changes such as hyaline casts, glomerular thickening and moderate interstitial fibrosis and arteriolopathy, whereas irbesartan administration markedly prevented diabetic-induced renal morphological alterations. CONCLUSIONS: The present study suggests that oxidative stress/nitrosative stress is increased in the diabetic kidney and AT1 receptor blockade can prevent these changes. The results also suggest that in STZ-induced diabetic rats, the protective action of irbesartan might be mediated, at least in part, by its effect on tissue oxidant/antioxidant status.