Method for the diagnosis and treatment of essential primary hypertension

Abstract

The invention is in the field of molecular diagnosis of medical diseases and their treatment. More in particular, it provides methods and means for detecting hypertension, more in particular essential primary hypertension, even more in particular NOX5-dependent hypertension. The invention also provides methods for the treatment of hypertension, in particular essential primary hypertension, more in particular NOX5-dependent hypertension. The invention also provides theragnostics, wherein therapy is combined with diagnosis, more in particular wherein the level of NOX5 is determined in a sample from a subject and wherein the subject is treated with NOX5 inhibitors or compounds that decrease the levels of NOX5 if the NOX5 levels are above a certain threshold value. Further, the invention also provides theragnostics, wherein diagnosis is combined with therapy, more in particular wherein the (plasma) level of NOX5 is determined in a sample from a subject and wherein the subject is treated with NOX5 inhibitors or compounds that reverse the result of NOX5 activity in the subject, when the determined NOX5 level is exceeding a predetermined threshold level. Finally, the invention relates to an animal model suitable for developing diagnostic methods and therapeutic treatments for NOX5-dependent hypertension.

1 . A method for detection of a hypertension endotype in a human patient suffering from essential arterial hypertension, wherein said endotype is defined by an increased level of circulating NADPH oxidase 5 protein (NOX5) compared to the level of circulating NOX5 in a human subject not suffering from hypertension, 
       the method comprising the steps of:
 (a) obtaining a fluid sample from the human patient who suffers from essential arterial hypertension, selected from the group comprising plasma, blood and serum, wherein the fluid sample comprises circulating endothelial microparticles; 
 (b) isolating the endothelial microparticles from the fluid sample provided in step (a); and 
 (c) measuring NOX5 in the endothelial microparticles of step (b) using a protein detection assay and determining the concentration of NOX5 in the fluid sample in pg NOX5 per ml fluid sample, 
 wherein it is concluded that the human patient suffers from the hypertension endotype if the concentration of NOX5 as determined in step (c) is at least 160 pg NOX5 per ml of the fluid sample. 
 
     
     
         2 . The method for detection according to  claim 1 , wherein the fluid sample is a plasma sample. 
     
     
         3 . The method for detection according to  claim 1 , wherein the human patient suffers from hypertension as defined as a systolic blood pressure of at least 140 mmHg, a diastolic blood pressure of at least 90 mmHg, or use of an antihypertensive drug. 
     
     
         4 . The method for detection according to  claim 1 , wherein the human patient does not have a history or clinical evidence of any of: angina, myocardial infarction, congestive heart failure, peripheral vascular disease, inflammatory disease and any disease predisposing to vasculitis, and wherein the human subject does not have stage 4 or stage 5 chronic kidney disease. 
     
     
         5 .- 13 . (canceled) 
     
     
         14 . A method for the detection of a hypertension endotype in a human patient suffering from essential arterial hypertension, wherein said endotype is hypertension characterized by being
 accompanied by renal vascular leakage as established by the occurrence of microalbuminuria; or   associated with the risk for developing renal vascular leakage apparent as development of microalbuminuria,   
       the method comprising the steps of:
 (a) obtaining a fluid sample from the human patient who suffers from essential arterial hypertension, selected from the group comprising plasma, blood and serum, wherein the fluid sample comprises circulating endothelial microparticles; 
 (b) isolating the endothelial microparticles from the fluid sample provided in step (a); and 
 (c) measuring NADPH oxidase 5 protein (NOX5) in the endothelial microparticles of step (b) using a protein detection assay and determining the concentration of NOX5 in the fluid sample in pg NOX5 per ml fluid sample, 
 wherein it is concluded that the human patient has the hypertension endotype if the concentration of NOX5 is at least 160 pg NOX5 per ml of the fluid sample. 
 
     
     
         15 . The method for the detection according to  claim 14 , wherein the human patient has a systolic arterial blood pressure of at least 140 mmHg and a diastolic arterial blood pressure of at least 90 mmHg at two days. 
     
     
         16 . The method for the detection according to  claim 14 , wherein in step (a) the fluid sample is a plasma sample. 
     
     
         17 . The method for the detection according to  claim 14 , wherein in step (c) the protein detection assay is an enzyme-linked immumnsorbent assay. 
     
     
         18 .- 26 . (canceled) 
     
     
         27 . A method of use of a mouse with knocked-in human Nox5 gene to discover and develop therapeutics and methods for detection, for the use in NOX5-dependent hypertension in a subject. 
     
     
         28 . The method of use according to  claim 27 , wherein the mouse has an age of at least 68 weeks. 
     
     
         29 . The method of use according to  claim 27 , wherein the mouse is a 129/SV mouse. 
     
     
         30 . The method of use according to  claim 27 , wherein the mouse has a genetic background comprising 80% 129/SV. 
     
     
         31 . The method of use according to  claim 27 , wherein the mouse has a genetic background consisting of 80% 129/SV and 20% C57BI6. 
     
     
         32 . The method of use according to  claim 27 , wherein the knocked-in human Nox5 gene is regulated by promotor tie 2. 
     
     
         33 . The method of use according to  claim 27 , wherein human NOX5 is expressed in endothelial cells and white blood cells of the mouse. 
     
     
         34 . The method for the detection according to  claim 1 , wherein in step (c) the protein detection assay is an enzyme-linked immunosorbent assay.