Interaction of cyclosporine A and the renin-angiotensin system; new perspectives.
Despite extensive research, the exact mechanisms of cyclosporine A (CsA)-induced hypertension and nephrotoxicity remain obscure. Several lines of evidence suggest an involvement of the renin-angiotensin system (RAS) in CsA toxicity, but the issue is still controversial in more ways than one. Some interesting data of the interaction of CsA and RAS have been presented by us and others during the last years. In rats, activation of RAS by CsA is a consistent finding while the results from clinical studies show controversial results. The mechanisms of activation of RAS may be multifactorial. CsA increases renin release directly from juxtaglomerular cells. However, RAS activation may at least partly account for glomerular ischemia by vasoconstriction. A totally different view about the interaction of CsA and RAS has recently been presented. CsA antagonised the harmful effects of RAS over-expression on renal damage in double transgenic rats harbouring human renin and angiotensinogen genes. The protection was due to anti-inflammatory properties of CsA by inhibition of interleukin-6 and inducible nitric oxide synthase (iNOS) expression. Other studies have confirmed the inhibitory effect of CsA on iNOS. Calcium antagonists have been proposed to be the antihypertensive drugs of choice in treatment of CsA-induced hypertension because of their favourable haemodynamic effects on the kidneys. However, because angiotensin II plays a major role in the development of CsA-induced structural renal damage, pharmacological inhibition of RAS in CsA-treatment may have some beneficial effects beyond blood pressure control.
Lassila
M
M
Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, Finland. markus.lassila@helsinki.fi
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D002118:Calcium