Hypertension: focus on the renin-angiotensin-aldosterone system and beyond

Principal investigator: Dr. A.H. Jan Danser, Professor of Pharmacology

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

Companies we collaborate with:

  • Abbott
  • Actelion
  • AFFiRis
  • AstraZeneca
  • Genkyotex
  • Lanthiopharma
  • Medivir
  • Novartis
  • Pfizer
  • Roche Diagnostics
  • Unilever
  • Vitae Pharmaceuticals

  • References
    1. Campbell DJ, Nussberger J, Stowasser M, Danser AHJ, Morganti A, Frandsen E, Ménard J. Activity assays and immunoassays for plasma renin and prorenin: information provided and precautions necessary for accurate measurement. Clin Chem 2009;55:867-877.

    2. Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, Danser AHJ, Boomsma F, Frandsen E, Parving HH. Optimal antiproteinuric dose of aliskiren in type 2 diabetes mellitus: a randomised crossover trial. Diabetologia 2010;53:1576-1580.

    3. Balcarek J, Sevá Pessôa B, Bryson C, Azizi M, Ménard J, Garrelds IM, McGeehan G, Reeves RA, Griffith SG, Danser AHJ, Gregg R. Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition. Hypertension 2014;63:942-950.

    4. Schilders JE, Wu H, Boomsma F, van den Meiracker AH, Danser AHJ. Renin-angiotensin system phenotyping as a guidance toward personalized medicine for ACE inhibitors: can the response to ACE inhibition be predicted on the basis of plasma renin or ACE? Cardiovasc Drugs Ther 2014;28:335-345.

    5. Jansen PM, van den Born BJ, Frenkel WJ, de Bruijne EL, Deinum J, Kerstens MN, Smulders YM, Woittiez AJ, Wijbenga JA, Zietse R, Danser AHJ, van den Meiracker AH. Test characteristics of the aldosterone-to-renin ratio as a screening test for primary aldosteronism. J Hypertens 2014;32:115-126.

    6. Verwoert GC, Hofland J, Amin N, Mattace-Raso FU, Sijbrands EJ, Hofman A, van den Meiracker AH, Uitterlinden AG, van Duijn CM, de Jong FH, Danser AHJ. Expression and gene variation studies deny association of human HSD3B1 gene with aldosterone production or blood pressure. Am J Hypertens 2015;28:113-120.

    7. Roksnoer LCW, Verdonk K, Garrelds IM, van Gool JMG, Zietse R, Hoorn EJ, Danser AHJ. Methodologic issues in the measurement of urinary renin. Clin J Am Soc Nephrol 2014;9:1163-1167.

    8. van der Lubbe N, Jansen PM, Salih M, Fenton RA, van den Meiracker AH, Danser AHJ, Zietse R, Hoorn EJ. The phosphorylated sodium chloride cotransporter in urinary exosomes is superior to prostasin as a marker for aldosteronism. Hypertension 2012;60:741-748.

    9. Danser AHJ, Anand P. The angiotensin II type 2 receptor for pain control. Cell 2014;157:1504-1506.

    10. te Riet L, van den Heuvel M, Peutz-Kootstra CJ, van Esch JHM, van Veghel R, Garrelds IM, Musterd-Bhaggoe U, Bouhuizen AM, Leijten FP, Danser AHJ, Batenburg WW. Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats. Am J Physiol Renal Physiol 2014;306:F1179-F1189.

    11. Batenburg WW, Jansen PM, van den Bogaerdt AJ, Danser AHJ. Angiotensin II-aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase. Cardiovasc Res 2012;94:136-143.

    12. Lankhorst S, Kappers MHW, van Esch JHM, Smedts FM, Sleijfer S, Mathijssen RH, Baelde HJ, Danser AHJ, van den Meiracker AH. Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: preclinical study. Hypertension 2014;64:1282-1289.

    13. Kappers MHW, Smedts FM, Horn T, van Esch JHM, Sleijfer S, Leijten F, Wesseling S, Strevens H, Danser AHJ, van den Meiracker AH. The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system. Hypertension 2011;58:295-302.

    14. Moltzer E, te Riet L, Swagemakers SM, van Heijningen PM, Vermeij M, van Veghel R, Bouhuizen AM, van Esch JH, Lankhorst S, Ramnath NW, de Waard MC, Duncker DJ, van der Spek PJ, Rouwet EV, Danser AHJ, Essers J. Impaired vascular contractility and aortic wall degeneration in fibulin-4 deficient mice: effect of angiotensin II type 1 (AT1) receptor blockade. PLoS One 2011;6:e23411.