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 [3H]-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 125I-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 125I-Ang II binding was reversed by the removal of extracellular glucose, suggesting a role for glucose specificity. The high glucose-induced down-regulation of 125I-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 125I-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 [3H]-AA release, and down-regulation of 125I-Ang II binding. W-7 and KN-62 also blocked the high glucose-induced increase of [3H]-AA release and down-regulation of 125I-Ang II binding. However, phospholipase A2 inhibitor did not block high glucose-induced activation of p44/42 MAPK.
Bibliographical noteFunding Information:
This study was financially supported by the project (01-PJ1-PG3-20700-0010) from the Ministry of Health and Welfare (to H.J. Han).
- Angiotensin II receptor
- Cell signaling
- Diabetic nephropathy
- Mitogen-activated protein kinase
- Phospholipase A
- Protein kinase C
ASJC Scopus subject areas