Method and compositions for the treatment and detection of endothelin-1 related kidney diseases

Abstract

The present application relates to methods of treating HIV-associated nephropathy (HIVAN) and/or focal segmental glomerulosclerosis (FSGS) using endothelin-1 (ET-1) antagonists. The application further relates to a composition for the treatment of HIVAN and/or FSGS. A kit for detecting the presence of ET-1 or ET-1-associated biomarker in a biological sample is also disclosed.

What is claimed is: 
     
         1 . A method of treating HIV-associated nephropathy (HIVAN) or focal segmental glomerulosclerosis (FSGS), comprising administering to a mammalian subject an effective amount of a composition comprising an ET-1 antagonist, wherein the subject has an increased level of ET-1 compared to a control subject. 
     
     
         2 . The method of  claim 1 , wherein the control subject is an HIV positive subject. 
     
     
         3 . The method of  claim 1 , wherein the ET-1 antagonist is a small molecule that binds to ET-1 or ET-1 A . 
     
     
         4 . The method of  claim 1 , wherein the ET-1 antagonist is selected from the group consisting of sitaxentan, ambrisentan, atrasentan, BQ-123, bosentan and tezosentan. 
     
     
         5 . The method of  claim 1 , wherein the ET-1 antagonist is administered by a local infusion into a kidney of the subject. 
     
     
         6 . A method for diagnosis of Nephropathy in a subject, comprising:
 comparing a level of an ET-1-associated biomarker in a biological sample obtained from the subject to a threshold level; and   making a diagnosis based a result from the comparing step.   
     
     
         7 . The method of  claim 6 , wherein the biological sample is blood, plasma, urine, saliva or tissue. 
     
     
         8 . The method of  claim 6 , wherein the threshold level is a plasma ET-1 level at about 4 pg/ml and the subject is deemed to have a high risk of HIVAN and/or FSGS, if the plasma ET-1 level in the subject is higher than the threshold level. 
     
     
         9 . The method of  claim 6 , wherein the threshold level is a plasma ET-1 level at about 4.5 pg/ml and the subject is deemed to have a high risk of HIVAN and/or FSGS, if the plasma ET-1 level in the subject is higher than the threshold level. 
     
     
         10 . The method of  claim 6 , wherein said ET-1-associated biomarker is ET-1. 
     
     
         11 . The method of  claim 6 , wherein the level of the ET-1-associated biomarker is the ppET-1 mRNA level in peripheral blood derived macrophages that are harvested from the subject and cultured in the presence of HIV Nef. 
     
     
         12 . The method of  claim 6 , further comprising determining the level of the ET-1-associated biomarker in the biological sample for the subject. 
     
     
         13 . The method of  claim 6 , wherein said nephropathy is select from the group consisting of glomerulopathy, glomerulitis, glomerulonephritis, glomerulonephrosis, tubulitis, HIVAN, FSGS, Diabetic nephropathy, sickle cell nephropathy, renovascular hypertension, drug induced nephropathy, nephron loss, hyperfiltration, chronic pyelonephritis, Type I RPG/Type II hypersensitivity, Goodpasture's syndrome, Type II RPG/Type III hypersensitivity, Lupus (DPN), IgA/Berger's nephropathy, Wegener's granulomatosis, Microscopic polyangiitis, RTA (RTA 2), Fanconi syndrome, Bartter syndrome, Gitelman syndrome, Liddle's syndrome, RTA (RTA 1), diabetes insipidus (Nephrogenic), renal papilla, renal papillary necrosis, major calyx/pelvis, hydronephrosis, pyonephrosis, reflux nephropathy, acute tubular necrosis, interstitial nephritis, pyelonephritis, danubian endemic, familial nephropathy, renal failure, acute renal failure, chronic renal failure, uremic pericarditis, uremia, renal artery stenosis, renal ischemia, hypertensive nephropathy, renovascular hypertension, analgesic nephropathy, renal osteodystrophy, nephroptosis, and Abderhalden-Kaufmann-Lignac syndrome. 
     
     
         14 . The method of  claim 6 , wherein said nephropathy is HIVAN or FSGS. 
     
     
         15 . A composition for the treatment of HIVAN or FSGS, said composition comprising an ET-1 antagonist and a pharmaceutically acceptable carrier. 
     
     
         16 . The composition of  claim 15 , wherein the ET-1 antagonist is a small molecule that binds to ET-1 or ET-1 A . 
     
     
         17 . The composition of  claim 16 , wherein the ET-1 antagonist is selected from the group consisting of sitaxentan, ambrisentan, atrasentan, BQ-123, bosentan and tezosentan. 
     
     
         18 . The composition of  claim 16 , wherein the composition is formulated for a route of administration selected from the group consisting of intravenous, intramuscular, nasal, transdermal, transmucosal, buccal, sublingual, oral, subdermal, or combination thereof. 
     
     
         19 . A kit for detecting the presence of an ET-1-associated biomarker in a biological sample, wherein said kit comprises one or more reagents suitable for measuring the ET-1-associated biomarker in the biological sample; and instructions for using said kit to detect said ET-1-associated biomarker, wherein the biological sample is blood, plasma, urine, saliva or tissue. 
     
     
         20 . The kit of  claim 19 , wherein the reagents comprise an antibody, nucleic acid, or fragment thereof, wherein the antibody, nucleic acid, or fragment thereof specifically binds to the ET-1-associated biomarker.