[Abnormal inositol phospholipid metabolism as a main factor causing pericyte drop-out in diabetic retinopathy].
The biochemical basis of pericyte loss in early diabetic retinopathy is still an open question. In studies on the mechanism by which retinal pericytes degenerate, we first established a bovine retinal capillary pericyte (BRCP) cell line. Subcultured BRCP grown in high (10-40 mmol/L) glucose media were used as an experimental model. We found that high concentrations of glucose suppress the mitotic rate and cell birth rate of cultured BRCP. High concentrations of glucose inhibit myo-inositol transport and result in decreased intracellular myo-inositol content. This inhibition can be partially reversed by sorbinil, an aldose reductase inhibitor (ARI). Myo-inositol is a precursor of inositol phospholipids (IPLs), whose metabolism is responsible for a number of signal transduction processes. Phosphoinositidase (PIase) cleaves the phosphodiester bond of phosphotidylinositol 4,5 diphosphate (PIP2) to produce two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DG). Further experiments showed that IP3 and DG synergistically activate BRCP proliferation in vitro. High concentrations of glucose altered the formation of both IPLs and inositol phosphate esters (IPEs) in an organ culture of retinal microvessels. This alteration can be reversed by adding either high concentrations of myo-inositol or ARI to the medium. PIase activity was attenuated to 82% or 55% when glucose in the growth medium was increased from 5 to 15 or 30 mmol/L, respectively. When IPLs from BRCP were analyzed by HPLC and TLC, we observed the reduction of three IPLs, including the substrate of PIase, PIP2.(ABSTRACT TRUNCATED AT 250 WORDS)
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D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D002417:Cattle; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000209:etiology* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007294:Inositol / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism
D007093:Imidazoles; D048289:Imidazolidines; D010716:Phosphatidylinositols; D007294:Inositol; D013012:Sorbitol; D000449:Aldehyde Reductase; C026411:sorbinil; D005947:Glucose