The antihypertensive market was valued at $31 billion in 2003. Although the development of generic equivalents has reduced the market value of the four major antihypertensive classes, the angiotensin II receptor blocker class has experienced strong growth (see Antihypertensives - Together We Stand, Divided We Fail). The kidney plays an important role in regulating blood pressure and the renal enzyme renin is a target for what is expected to be the next blockbuster class of anti-hypertensives. The report highlighted here identifies a further renal enzyme, renalase that may be another target for the treatment of hypertension. Renalase may be particularly important in the increasingly problematic group of patients with end-stage renal disease.

The antihypertensive market was valued at $31 billion in 2003. Although the development of generic equivalents has reduced the market value of the four major antihypertensive classes (ACE inhibitors, calcium channel blockers, beta blockers and diuretics), market growth of the angiotensin II receptor blocker (ARB) class has been experienced. Analysts predict that the strong growth of the ARB Diovan (valsartan) will make it the leading global antihypertensive by 2007 with estimated sales of $3.3 billion.

Due to the financial incentive in developing a drug that can demonstrate an advance in antihypertensive efficacy over existing products, and the continued growth in the worldwide prevalence of hypertension, the antihypertensive market continues to attract a high level of R&D investment from the many pharmaceutical companies that are represented in this market (for a full analysis of R&D and market activity within the hypertension arena see Antihypertensives - Together We Stand, Divided We Fail). Resulting from considerable research efforts, oral renin inhibitors are being developed and the lead candidate in this field, Speedel/Novaritis' phase III aliskiren, is expected to be a blockbuster.

The kidney is the most important site for the release of renin, an enzyme that cleaves angiotensinogen to angiotensin I. By targeting the Renin Angiotensin System earlier than either ACE inhibitors or ARBs, it is likely that the renin inhibitors will have potentially greater efficacy and fewer side effects. It is expected that aliskiren will have its US and EU launch in late 2006 and analysts estimate that sales will exceed $1 billion in sales by 2008 and reach total sales of $3.6 billion by 2012.

The JCI paper highlighted here identifies a further molecular target expressed in the renal system for the treatment of hypertension. Xu et al report on the discovery of a novel flavin adenine dinucleotide-dependent (FAD-dependent) amine oxidase termed renalase that is secreted into the blood by the kidney, and which metabolizes circulating catecholamines thus regulating blood pressure.

Xu et al identified renalase by screening the human genome for cDNA clones coding for novel secretory proteins; renal expression of each clone thus identified was then investigated. The clone encoding renalase was highly expressed in the human kidney and further studies demonstrated the presence of renalase in renal glomeruli, proximal tubules, and cardiomyocytes.

Structural analysis revealed that renalase contains an amino oxidase domain and the protein was found to specifically metabolize cathecholamines, with dopamine being the preferred substrate, followed by epinephrine, and then norepinephrine. In vivo studies found that recombinant renalase reduced systolic, diastolic, and mean arterial pressure by modifying cardiac contractility. Heart rate was also reduced but peripheral vascular resistance remained unchanged.

The present study is of interest since it suggests that increasing the endogenous expression of renalase or administering recombinant renalase (or renalase mimics) may offer an new approach to the treatment of hypertension. This may be of particular relevance to patients with renal disease. Renal disease is associated with a marked increase in cardiovascular disease and although the mechanism underlying this relationship is unclear plasma dopamine and norepinephrine levels are consistently increased in patients with end-stage renal disease. The expression of renalase deserves to be measured in these patients and if reduced levels are found enzyme replacement therapy may well be indicated.

End-stage renal disease is a growing problem and it has been estimated that well over half a million patients will be treated for the condition by 2010. Treatment also accounts for a growing portion of healthcare budgets; in the US for example end-stage renal disease takes up nearly 7% of the medicare budget (for full details see the USRD report from 2004). The growing epidemic in end-stage renal disease is due in part to its particularly high incidence amongst diabetics; indeed this patient group accounts for the greatest number of patients with renal failure in the US and Europe. Despite the efforts to address the increasing incidence of both type 1 and type 2 diabetes, the diabetic population is set to increase by 72% between 2003 and 2025 (Diabetic Nephropathy: Prevalence, Progression, Prevention and Potential). Identifying the potential of new therapeutics related to renalase should therefore examined.

Entry date Thursday, June 02, 2005

J Clin Invest. 2005 May 2;115(5):1275-1280. Epub 2005 Apr 7

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