ANGIOTENSIN-II STIMULATES EXPRESSION OF THE CHEMOKINE RANTES IN RAT GLOMERULAR ENDOTHELIAL-CELLS - ROLE OF THE ANGIOTENSIN TYPE-2 RECEPTOR

Glomerular influx of monocytes/macrophages (M/M) occurs in many immune -and non-immune-mediated renal diseases. The mechanisms targeting MIM into the glomerulus are incompletely understood, but may involve stimu lated expression of chemokines. We investigated whether angiotensin II (ANG II) induces the chemokine RANTES in cultured glomerular endothel ial cells of the rat and in vivo. ANG II stimulated mRNA and protein e xpression of RANTES in cultured glomerular endothelial cells. The ANG II-induced RANTES protein was chemotactic for human monocytes. Surpris ingly, the ANG II-stimulated RANTES expression was transduced by AT(2) receptors because the AT(2) receptor antagonists PD 123177 and CGP-42 112A, but not an A(1) receptor blocker, abolished the induced RANTES s ynthesis. Intraperitoneal infusion of ANG II (500 ng/h) into naive rat s for 4 d significantly stimulated glomerular RANTES mRNA and protein expression compared with solvent-infused controls. Immunohistochemistr y revealed induction of RANTES protein mainly in glomerular endothelia l cells and small capillaries. Moreover, ANG II-infused animals exhibi ted an increase in glomerular ED-1-positive cells compared with contro ls. Oral treatment with PD 123177 (50 mg/liter drinking water) attenua ted the glomerular M/M influx without normalizing the slightly elevate d systolic blood pressure caused by ANG II infusion, suggesting that t he effects on blood pressure and RANTES induction can be separated. We conclude that the vasoactive peptide ANG II may play an important rol e in glomerular chemotaxis of MIM through local induction of the chemo kine RANTES. The observation that the ANG II-mediated induction of RAN TES is transduced by AT(2) receptors may influence the decision as to which substances might be used for the therapeutic interference with t he activity of the renin-angiotensin system.