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  • Title: High glucose down-regulates angiotensin II binding via the PKC-MAPK-cPLA2 signal cascade in renal proximal tubule cells.
    Author: Park SH, Woo CH, Kim JH, Lee JH, Yang IS, Park KM, Han HJ.
    Journal: Kidney Int; 2002 Mar; 61(3):913-25. PubMed ID: 11849446.
    Abstract:
    BACKGROUND: It has been reported that renal renin-angiotensin system contributes to the development of diabetic nephropathy. However, the mechanism of angiotensin II receptor regulation in diabetic condition has not been elucidated. METHODS: The effects of high glucose on [(3)H]-arachidonic acid (AA) release and angiotensin II (Ang II) binding and its related signal pathway were examined in primary cultured rabbit renal proximal tubule cells (PTCs). RESULTS: High glucose down-regulated (125)I-Ang II binding from 12 hours and this response was sustained over 48 hours. Thus, the treatment of 25 mmol/L glucose for 48 hours was used for this study. High glucose-induced down-regulation of (125)I-Ang II binding was reversed by the removal of extracellular glucose, suggesting a role for glucose specificity. The high glucose-induced down-regulation of (125)I-Ang II binding was blocked by mepacrine, AACOCF3, phospholipase A2 inhibitors, indomethacin, ibuprofen, and cyclooxygenase inhibitors. Indeed, high glucose significantly increased prostaglandin E2 synthesis. In addition, the high glucose-induced AA release was blocked by PD 98059, a p44/42 mitogen-activated protein kinase (MAPK) inhibitor. PD 98059 also prevented the down-regulation of (125)I-Ang II binding by high glucose, suggesting a role for p44/42 MAPK. Indeed, high glucose significantly increased p44/42 MAPK activity after the 15-minute time point. Protein kinase C (PKC) inhibitor blocked high glucose-induced activation of p44/42 MAPK, increase of the [(3)H]-AA release, and down-regulation of 125I-Ang II binding. W-7 and KN-62 also blocked the high glucose-induced increase of [(3)H]-AA release and down-regulation of (125)I-Ang II binding. However, phospholipase A2 inhibitor did not block high glucose-induced activation of p44/42 MAPK. CONCLUSION: High glucose down-regulates (125)I-Ang II binding via the PKC-MAPK-cPLA2 signal pathway.
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