Combination of aspirin with telmisartan suppresses the augmented TGFbeta/smad signaling during the development of streptozotocin-induced type I diabetic nephropathy

Chem Biol Interact. 2010 Apr 29;185(2):137-42. doi: 10.1016/j.cbi.2010.03.008. Epub 2010 Mar 9.

Abstract

Diabetic nephropathy (DN) is the most common indication for the development of end stage renal diseases. Inflammation is increasingly seen as the core process in the development of diabetes. Inflammatory markers e.g. NFkappaB (p65 levels), TNFalpha, COX-2 and TGFbeta-smad signaling are the key elements in the development of DN. Renin-angiotensin system suppressors like telmisartan have been used to treat DN, but they are not able to prevent completely because of development of resistance against them. Anti-inflammatory agents like, aspirin acts through both COX dependent and COX independent pathways. Hence, we thought that combining aspirin with telmisartan will be better therapeutic option in preventing the progression of nephropathy in diabetes. In the present study we studied the effect of this combination on inflammatory markers [COX-2, NFkappaB (p65 levels), TNFalpha], TGFbeta-smad expression in preventing the progression of streptozotocin-induced type I diabetic nephropathy. Treatment of aspirin significantly prevented the progression of nephropathy and inhibited the augmented COX-2, NFkappaB (p65 levels), TNFalpha, and TGFbeta-smad expression. Combination of aspirin with telmisartan resulted in a further decrease in the development of nephropathy and inflammatory markers in comparison to aspirin alone treatment. This is the first report which shows that aspirin in combination with telmisartan is more proficient in the treatment of diabetic nephropathy than any single drug therapy and involves the change in expression of inflammatory markers and TGFbeta-smad signaling.

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Aspirin / pharmacology*
  • Aspirin / therapeutic use
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Benzoates / pharmacology*
  • Benzoates / therapeutic use
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetic Nephropathies / chemically induced
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Smad Proteins / metabolism*
  • Streptozocin / administration & dosage
  • Streptozocin / toxicity
  • Telmisartan
  • Transforming Growth Factor beta / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzimidazoles
  • Benzoates
  • NF-kappa B
  • Smad Proteins
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Streptozocin
  • Cyclooxygenase 2
  • Aspirin
  • Telmisartan