Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension

Hypertension and kidney damage in the double transgenic pat (dTGR) harborin g both human renin and human angiotensinogen genes are dependent on the hum an components of the renin angiotensin system. We tested the hypothesis tha t monocyte infiltration and increased adhesion molecule expression are invo lved in the pathogenesis of kidney damage in dTGR, We also evaluated the ef fects of long-term angiotensin-converting enzyme (ACE) inhibition, AT(1) bl ockade, and human renin inhibition on monocyte recruitment and inflammatory response in dTGR. Systolic blood pressure and 24-hour albuminuria were mar kedly increased in 7-week-old dTGR as compared with age-matched normotensiv e Sprague Dawley rats. We found a significant monocyte/macrophage infiltrat ion in the renal perivascular space and increased expression of intercellul ar adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM -1) in the interstitium, intima, and adventitia of the small renal vessels, alpha(L)beta(2) integrin and alpha(4)beta(1) integrin, the corresponding l igands for ICAM-1 and VCAM-1, were also found on infiltrating monocytes/mac rophages. The Expression of plasminogen activator inhibitor-1 and fibronect in in the kidneys of dTGR were increased and distributed similarly to ICAM- 1. In 4-week-old dTGR, long-term treatment with ACE inhibition (cilazapril) , AT(1) receptor blockade (valsartan), and human renin inhibition (RO 65-72 19) (each drug 10 mg/kg by gavage once a day for 3 weeks) completely preven ted the development of albuminuria. However, only cilazapril and valsartan were able to decrease blood pressure to normotensive levels. Interestingly, the drugs were all equally effective in preventing monocyte/macrophage inf iltration and the overexpression of adhesion molecules, plasminogen activat or inhibitor-1, and fibronectin in the kidney. Our findings indicate that a ngiotensin II causes monocyte recruitment and vascular inflammatory respons e in the kidney by blood pressure-dependent and blood pressure-independent mechanisms. ACE inhibition, AT(1) receptor blockade, and human renin inhibi tion all prevent monocyte/macrophage infiltration and increased adhesion mo lecule expression in the kidneys of dTGR.