Treatment of disorders associated with elevated blood glucose or blood pressure

Abstract

The present invention relates to methods for treating or delaying the onset of pathologies associated with elevated blood glucose and/or elevated blood pressure. The methods are directed to modulating, regulating, or inhibiting the expression or activity of Connective Tissue Growth Factor (CTGF) or fragments thereof.

1 . A method of identifying an agent that modulates CTGF induction by glucose, the method comprising 
 (a) culturing a first cell population in media containing high glucose;    (b) culturing a second cell population in media containing high glucose and an agent;    (c) measuring CTGF level in the culture media from the first and second cell populations; and    (d) comparing CTGF level in the culture media from the second cell population to CTGF level in the culture media from the first cell population, wherein a difference in CTGF level between the second and first cell populations is indicative of an agent that modulates CTGF induction by glucose.    
     
     
         2 . The method of  claim 1 , wherein the glucose concentration in the media containing high glucose is at least about 20 mM.  
     
     
         3 . The method of  claim 1 , wherein the glucose concentration in the media containing high glucose is at least about 35 mM.  
     
     
         4 . The method of  claim 1 , wherein the first and second cell populations are of the same cell type and are fibroblasts.  
     
     
         5 . The method of  claim 4 , wherein the fibroblasts are kidney mesangial cells.  
     
     
         6 . An agent that modulates CTGF induction by glucose, wherein the agent is identified by the method of  claim 1 .  
     
     
         7 . The agent of  claim 6 , wherein the agent additionally increases cyclic nucleotide level in a cell.  
     
     
         8 . A method of reducing expression of CTGF in a subject having elevated blood glucose, the method comprising administering the agent of  claim 6  to a subject having or at risk for having high blood glucose.  
     
     
         9 . A method of identifying an agent that modulates CTGF induction associated with mechanical stress, the method comprising 
 (a) culturing a first cell population in the absence of agent under conditions that place the cells under increased mechanical stress;    (b) culturing a second cell population in the presence of agent under conditions that place the cells under increased mechanical stress;    (c) measuring CTGF level in the culture media from first and second cell populations; and    (d) comparing CTGF level in the culture media from the second cell population to CTGF level in the culture media from the first cell population, wherein a difference in CTGF level between the second and first cell populations is indicative of an agent that modulates CTGF induction associated with mechanical stress.    
     
     
         10 . The method of  claim 9 , wherein mechanical stress is cyclic stretching of cells up to and including 19% maximum elongation.  
     
     
         11 . The method of  claim 9 , wherein the first and second cell populations are of the same cell type and are fibroblasts.  
     
     
         12 . The method of  claim 11 , wherein the fibroblasts are kidney mesangial cells.  
     
     
         13 . An agent that modulates CTGF induction associated with mechanical stress, wherein the agent is identified by the method of  claim 9 .  
     
     
         14 . A method of reducing expression of CTGF in a subject having elevated blood pressure, the method comprising administering the agent of  claim 13  to a subject having elevated blood pressure.  
     
     
         15 . A method of treating or delaying onset of a disorder associated with elevated blood glucose, the method comprising administering to a subject in need an effective amount of an agent that modulates, regulates, or inhibits the expression or activity of CTGF or fragments thereof.  
     
     
         16 . The method of  claim 15 , wherein the subject has or is at risk of having hyperglycemia.  
     
     
         17 . The method of  claim 15 , wherein the agent is an antibody that specifically binds to CTGF or fragments thereof.  
     
     
         18 . The method of  claim 15 , wherein the agent is an antisense oligonucleotide that specifically binds to a polynucleotide sequence encoding CTGF.  
     
     
         19 . The method of  claim 15 , wherein the agent is a small molecule.  
     
     
         20 . The method of  claim 19 , wherein the agent additionally increases cyclic nucleotide levels in a cell.  
     
     
         21 . The method of  claim 15 , wherein the disorder is diabetes.  
     
     
         22 . The method of  claim 15 , wherein the disorder is a renal disorder.  
     
     
         23 . The method of  claim 22 , wherein the renal disorder is selected from the group consisting of glomerulosclerosis, glomerulonephritis, and diabetic nephropathy.  
     
     
         24 . The method of  claim 15 , wherein the disorder is an ocular disorder.  
     
     
         25 . The method of  claim 24 , wherein the ocular disorder is diabetic retinopathy.  
     
     
         26 . A method of treating or delaying onset of a disorder associated with elevated blood pressure, the method comprising administering to a subject in need an effective amount of an agent that modulates, regulates, or inhibits the expression or activity of CTGF or fragments thereof.  
     
     
         27 . The method of  claim 26 , wherein the agent is an antibody that specifically binds to CTGF or fragments thereof.  
     
     
         28 . The method of  claim 26 , wherein the agent is an antisense oligonucleotide that specifically binds to a polynucleotide sequence encoding CTGF.  
     
     
         29 . The method of  claim 26 , wherein the agent is a small molecule.  
     
     
         30 . The method of  claim 29 , wherein the agent additionally increases cyclic nucleotide levels in a cell.  
     
     
         31 . The method of  claim 26 , wherein the disorder is diabetes.  
     
     
         32 . The method of  claim 26 , wherein the disorder is a renal disorder.  
     
     
         33 . The method of  claim 32 , wherein the renal disorder is selected from glomerulosclerosis, glomerulonephritis, and diabetic nephropathy.  
     
     
         34 . The method of  claim 26 , wherein the disorder is an ocular disorder.  
     
     
         35 . The method of  claim 34 , wherein the ocular disorder is diabetic retinopathy.  
     
     
         36 . A method of treating or delaying onset of a disorder associated with renal hypertension, the method comprising administering to a subject in need an effective amount of an agent that modulates, regulates, or inhibits the expression or activity of CTGF or fragments thereof.  
     
     
         37 . The method of  claim 36 , wherein the agent is an antibody that specifically binds to CTGF or fragments thereof.  
     
     
         38 . The method of  claim 36 , wherein the agent is an antisense oligonucleotide that specifically binds to a polynucleotide sequence encoding CTGF.  
     
     
         39 . The method of  claim 36 , wherein the agent is a small molecule.  
     
     
         40 . The method of  claim 39 , wherein the agent additionally increases cyclic nucleotide levels in a cell.  
     
     
         41 . The method of  claim 36 , wherein the disorder is diabetes.  
     
     
         42 . The method of  claim 36 , wherein the disorder is a renal disorder.  
     
     
         43 . The method of  claim 42 , wherein the renal disorder is selected from glomerulosclerosis, glomerulonephritis, and diabetic nephropathy.