The Renin-Angiotensin System and MS

The renin-angiotensin system (RAS) was first studied for its role in regulation of the cardiovascular system and drugs that modulate the RAS are now widely used to treat high blood pressure, myocardial infarction and stroke. More recently, it has become apparent that components of the RAS also mediate inflammatory processes and two recently published studies have now expanded on the link between the RAS and multiple sclerosis (MS). A team led by researchers at Stanford University School of Medicine found that multiple sclerosis lesions from brains of MS patients had elevated levels of both the angiotensin I receptor (AT₁R) and angiotensin converting enzyme (ACE). The team then showed that treatment with the ACE inhibitor, lisinopril, or the AT₁R antagonist, candesartan, could prevent the development of experimental autoimmune encephalomyelitis (EAE) in mice and, perhaps more importantly, reverse the symptoms of established disease. Reduced activation of AT₁R was shown to increase the number of T_reg cells in the CNS and suppress TH1/TH17-mediated immune responses to autoantigens.

The study is published in the online early edition of PNAS.

The second study, by researchers in Germany and also published in the online early edition of PNAS, showed that renin, ACE and AT₁R were all up-regulated in the inflamed spinal cord and immune system, including antigen presenting cells (APC), of mice with EAE. Pretreatment with the renin inhibitor, aliskiren; the ACE inhibitor, enalapril; or the AT₁R antagonist, losartan, reduced the severity of EAE symptoms and losartan was also found to ameliorate the course of established disease. Blockade of AT₁R was found not to have a direct effect on T-cell responses but to significantly reduce APC in the spinal cord and immune organs, and to reduce cytokine-induced APC migration.

Since drugs that modulate the RAS have been used in millions of people around the world and have few side effects, the researchers hope that clinical trials to test their effectiveness in MS patients should be straightforward to carry out.