2-Chloroadenosine reverses hyperglycemia-induced inhibition of phosphoinositide synthesis in cultured human retinal pigment epithelial cells and prevents reduced nerve conduction velocity in diabetic rats.
The effect of the adenosine (AD) analog 2-chloroadenosine (C-AD) on glucose-induced inhibition of phosphoinositide synthesis was studied in human retinal pigment epithelial (RPE) cells by monitoring the level of the phosphatidylinositol (PI) synthase substrate, cytidine diphosphate diglyceride (CDP-DG). In high-aldose reductase (AR)-expressing RPE 91 cells, C-AD decreased CDP-DG at 5 mmol/L glucose and reversed the increase by 20 mmol/L glucose. AD deaminase (ADA), which inactivates endogenously released AD, potentiated the hyperglycemia-induced increase in CDP-DG. Theophylline, an AD-A1 and AD-A2 receptor antagonist, caused an increase in CDP-DG at 20 mmol/L glucose. C-AD did not alter CDP-DG in low-AR-expressing RPE 45 cells, but did decrease CDP-DG after cells were conditioned in 300 mmol/L glucose for 1 week (which induces AR). The mechanism by which AD regulates PI synthase in cells with high AR activity is unknown, but it is independent of Gi or Gs proteins, adenylate cyclase and phospholipase C (PLC) activation, myo-inositol (MI) uptake, or MI efflux. Administration of C-AD to streptozotocin-induced diabetic rats prevented the slowing of motor nerve conduction velocity (MNCV). Thus, AD derivatives, which reverse a glucose-induced deficit in phosphoinositide metabolism, might serve as a useful pharmacological tool to intervene in hyperglycemia-induced diabetic complications.
Kato
K
K
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0354, USA.
Thomas
T P
TP
Stevens
M J
MJ
Greene
D A
DA
Nakamura
J
J
D015762:2-Chloroadenosine / Q000494:pharmacology*; D000241:Adenosine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D009431:Neural Conduction / Q000502:physiology*; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism; D010738:Type C Phospholipases / Q000502:physiology
D008565:Membrane Proteins; D010716:Phosphatidylinositols; D015762:2-Chloroadenosine; D000449:Aldehyde Reductase; D017855:Transferases (Other Substituted Phosphate Groups); C496766:CDIPT protein, human; D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; C496767:Cdipt protein, rat; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D005947:Glucose; D000241:Adenosine