Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats.

Abstract

To investigate the role of angiotensin II (Ang II) in hypertension-induced tissue injury, we gave TCV-116 (1 mg/kg per day PO), a nonpeptide Ang II type I receptor antagonist, or enalapril (10 mg/kg per day PO) to deoxycorticosterone acetate (DOCA)-salt hypertensive rats for 3 weeks and examined the effects on tissue mRNA levels for transforming growth factor-01 (TGF-/31) and extracellular matrix components. Tissue mRNA levels were measured by Northern blot analysis. Renal mRNA levels for TGF-/31; types I, III, and IV collagen; and fibronectin in DOCA-salt hypertensive rats were increased by severalfold (P<.01) compared with sham-operated rats. In the aorta of DOCAsalt hypertensive rats, TGF-01 and fibronectin mRNA levels were increased, but types I, III, and IV collagen mRNAs did not increase. In the heart, increased mRNA was found only for fibronectin. Thus, these gene expressions are regulated in T he mechanism of development of hypertensionmediated renal injury remains to be determined, although hypertensive nephrosclerosis is one of the most important causes of end-stage renal failure. 13 Investigations on the effect of angiotensinconverting enzyme (ACE) inhibitors 48 or angiotensin II (Ang II) receptor antagonists 811 on various renal diseases in humans and animals indicate that the reninangiotensin system (RAS) participates in progressive renal injury as well as hypertension. Hemodynamic effects, such as the reduction of intraglomerular pressure by inhibition of the RAS, have been shown to contribute to a renal protective effect. 4 -5 ' 10 However, recent studies have shown that the mechanism of renal protection by ACE inhibitors can also be partly attributed to unknown mechanisms other than the hemodynamic effect. 12 -13 Furthermore, accumulating evidence shows that a local RAS exists in the kidney and supports the notion that an intrarenal RAS, independent of the

Angiotensin AT1 receptor antagonism and protection against cardiovascular end-organ damage

“…6,7 Candesartan cilexetil significantly reduced the damage in the renal tubules, the fibrinoid necrosis in the glomerulus and the interstitial fibrosis. 6,7 Renal cortical mRNA levels for TGF-␤1 and extracellular matrix components in the interstitium, fibronectin and collagen type I and III, in the control-DOCA/salt hypertensive rats were 2.4-, 3.9-, 4.6-and 3.1-fold higher, respectively, than those in the shamoperated rats. 7 Candesartan cilexetil significantly decreased the increase in these mRNA expressions.…”

“…10 The other hemisphere of the brain and left kidney were fixed in 10% neutral buffer formalin for histo-logical examination. 6,7 The brain from another series of rats was used for measurement of water and sodium contents. The mRNA levels for TGF-␤1 and extracellular matrix components in the interstitium and basement membrane in the renal cortex, left ventricle and aorta were also examined.…”

“…The mRNA levels for TGF-␤1 and extracellular matrix components in the interstitium and basement membrane in the renal cortex, left ventricle and aorta were also examined. 4,5,7 …”

“…6,7 Treatment with candesartan cilexetil for 3 weeks had little effect on BP and left ventricular weight. The urinary albumin level was significantly higher in the control-DOCA/salt hypertensive rats than in the sham-operated rats.…”

“…6 Atrophy of the epithelium, hypertrophy of the basement membrane, dilatation and hyaline casts were observed in the renal tubules. 6,7 Fibrinoid necrosis and atrophy of the capillary tuft were observed in the glomerulus. Fibrosis and infiltration of lymphocytes were observed in the interstitium.…”