Nehal M Elsherbiny1, Mohammed M H Al-Gayyar2, Khaled H Abd El Galil3. 1. Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, 35516, Egypt. 2. Department of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, 35516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia. Electronic address: mhgayyar@yahoo.com. 3. Dept of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
Abstract
AIMS: Inflammation plays significant roles in developing diabetic nephropathy (DN). Adenosine, natural purine nucleoside, acts as potent endogenous anti-inflammatory agent. Extracellular adenosine usually disappears quickly due to rapid uptake into adjacent cells. In this regard; we investigated putative reno-protective effects of dipyridamole, nucleoside transport inhibitor, by exploring its anti-inflammatory mechanisms in-vivo and in-vitro. MAIN METHODS: Daily 6mg/kg/day dipyridamole was given to six-weeks streptozotocin-induced diabetic rats over two-week period in presence/absence of 10mg/kg/day CGS15943, potent non selective adenosine receptors antagonist. Histological changes were assessed in kidney sections. Gene and protein expression of interleukin (IL)-1β, IL-10, IL-18, tumor necrosis factor (TNF)-α and intercellular adhesion molecule (ICAM)-1 was measured. Activation of apoptotic pathway was demonstrated by measuring the activity of caspase-3/8/9 and activation of c-Jun NH2-terminal kinases (JNK)-mitogen-activated-protein kinase (MAPK). In addition, all markers were measured in human mesangial cells cultured in high glucose. KEY FINDINGS: Diabetes induced marked changes in the glomerular and tubular structure including focal glomerulosclerosis with marked shrinkage of some glomerular tufts. Diabetes resulted in enhanced production of IL-1β, IL-18, TNF-α and ICAM-1 associated with reduced IL-10 protein level, leading to activation of caspases-3/8/9 and pJNK/JNK in-vivo and in-vitro. Dipyridamole treatment restored diabetes-induced reduction in adenosine levels and resulted in mild glomerular effects and vacuolation of tubular epithelium. Dipyridamole reduced the adhesion molecule, ICAM-1, and restored the normal balance between pro- and anti-inflammatory cytokines in-vivo and in-vitro. SIGNIFICANCE: Dipyridamole prevented the progression of DN by elevating endogenous levels of protecting adenosine, leading to reduction in inflammation and intrinsic apoptosis.
AIMS: Inflammation plays significant roles in developing diabetic nephropathy (DN). Adenosine, natural purine nucleoside, acts as potent endogenous anti-inflammatory agent. Extracellular adenosine usually disappears quickly due to rapid uptake into adjacent cells. In this regard; we investigated putative reno-protective effects of dipyridamole, nucleoside transport inhibitor, by exploring its anti-inflammatory mechanisms in-vivo and in-vitro. MAIN METHODS: Daily 6mg/kg/day dipyridamole was given to six-weeks streptozotocin-induced diabeticrats over two-week period in presence/absence of 10mg/kg/day CGS15943, potent non selective adenosine receptors antagonist. Histological changes were assessed in kidney sections. Gene and protein expression of interleukin (IL)-1β, IL-10, IL-18, tumor necrosis factor (TNF)-α and intercellular adhesion molecule (ICAM)-1 was measured. Activation of apoptotic pathway was demonstrated by measuring the activity of caspase-3/8/9 and activation of c-Jun NH2-terminal kinases (JNK)-mitogen-activated-protein kinase (MAPK). In addition, all markers were measured in human mesangial cells cultured in high glucose. KEY FINDINGS:Diabetes induced marked changes in the glomerular and tubular structure including focal glomerulosclerosis with marked shrinkage of some glomerular tufts. Diabetes resulted in enhanced production of IL-1β, IL-18, TNF-α and ICAM-1 associated with reduced IL-10 protein level, leading to activation of caspases-3/8/9 and pJNK/JNK in-vivo and in-vitro. Dipyridamole treatment restored diabetes-induced reduction in adenosine levels and resulted in mild glomerular effects and vacuolation of tubular epithelium. Dipyridamole reduced the adhesion molecule, ICAM-1, and restored the normal balance between pro- and anti-inflammatory cytokines in-vivo and in-vitro. SIGNIFICANCE: Dipyridamole prevented the progression of DN by elevating endogenous levels of protecting adenosine, leading to reduction in inflammation and intrinsic apoptosis.
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