Renin-angiotensin-aldosterone system (RAAS) blockers are the cornerstone in the treatment of hypertension, heart failure and proteinuric chronic kidney disease. Yet, morbidity and mortality of these diseases remain high, despite treatment with these blockers, i.e., renin inhibitors, ACE inhibitors, angiotensin II type 1 receptor antagonists and mineralocorticoid receptor antagonists. Initially, it was thought that this related to incomplete RAS blockade, e.g. due to renin upregulation and/or non-ACE-mediated angiotensin II formation. However, trials evaluating dual RAAS blockade to achieve near-complete suppression revealed an increased risk of adverse events (including hypotension, hyperkalemia and acute kidney injury) without additional benefit. Therefore, we still need new therapeutic strategies.
Our laboratory is a world-leader in the detection of RAAS components, and has developed a wide variety of assays to measure renin, prorenin, plasma renin activity and angiotensin in plasma, urine and tissues.1 As such we have been involved not only in the testing of many new drugs interfering with the RAAS,2,3 but also with the use of such measurements as a biomarker, to predict long-term outcome and/or to determine which drug should be used in which patient, for instance in patients with primary aldosteronism.4,5 This approach obviously also involved pharmacogenetics.6 Currently, we are evaluating the importance of urinary biomarkers, including RAAS components.7,8
Future treatment targets may involve the angiotensin II type 2 receptor,9 the (pro)renin receptor,10 non-mineralocorticoid aldosterone receptors,11 neutral endopeptidase, and endothelin-1.12 The latter is of particular importance given the occurrence of hypertension and renal injury during treatment of cancer patients with angiogenesis inhibitors like sunitinib, which increase endothelin-1.12 We have developed an animal model for sunitinib-induced hypertension, which simultaneously displays the renal abnormalities occurring in preeclampsia.13 In addition, we regularly make use of spontaneously hypertensive rats and renin-overexpressing TGR(mREN2)27 rats, if necessary made diabetic with streptozotocin.10 In fibulin-4 deficient mice, we currently study the effect of RAAS inhibition in aneurysm disease.14
State-of-the-art techniques to evaluate hemodynamic and kidney function in vivo (telemetry, metabolic cages, ultrasound, laser Doppler flow, microCT imaging, intravital microscopy) and ex-vivo (Langendorff heart preparation, Mulvany myograph), combined with a full range of biochemical and molecular-biological analyses, are available. In addition, we have access to human vessels (including coronary arteries11), and together with medical doctors from our institute we are able to perform detailed pharmacodynamic and pharmacokinetic cardiovascular studies in humans.4-6
