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目的噻唑烷二酮类药物是PPAR-γ的选择性配体,用于改善胰岛素抵抗,但因其可引起浮肿、钠潴留而使用受限。本研究探讨该类药物引起浮肿的机制及其传导通路。方法兔肾近曲小管在吡格列酮(0.03、0.3、3μmol/L)及PPAR-γ拮抗剂(5μmol/L GW9662)或MAPK抑制剂(10μmol/LPD98059)作用下,观察Na~+/HCO_3~-转运活动度及HCO_3~重1收率的变化,Western blot法测定ERK的磷酸化。结果 (1)0.3.mol/L吡格列酮刺激兔肾近曲小管Na~+和HCO_3~-的转运和重吸收,该刺激作用被MAPK抑制剂或PPAR-γ拮抗剂阻断。(2)0.3μmol/L吡格列酮引起ERK磷酸化,被MAPK抑制剂或PPAR-γ拮抗剂阻滞。结论在兔肾近曲小管,通过PPAR-γ依赖的ERK磷酸化介导吡格列酮引起的肾近曲小管Na~+和HCO_3~-的重吸收。
Objective Thiazolidinediones are PPAR-γ selective ligands for improving insulin resistance, but are limited in their use due to edema and sodium retention. This study explored the mechanism of these drugs cause edema and its conduction pathway. Methods The Na ~ + / HCO_3 ~ - transporter was observed in the proximal tubules of rabbit kidney under the action of pioglitazone (0.03,0.3 and 3μmol / L) and PPARγ antagonist (5μmol / L GW9662) or MAPK inhibitor (10μmol / LPD98059) Activity and HCO 3 ~ weight 1 yield changes, Western blot assay ERK phosphorylation. Results (1) Pioglitazone 0.3mol / L stimulated the translocation and reabsorption of Na ~ + and HCO_3 ~ - in proximal tubule of rabbits. The stimulation was blocked by MAPK inhibitor or PPAR-γ antagonist. (2) 0.3μmol / L pioglitazone caused phosphorylation of ERK, blocked by MAPK inhibitor or PPAR-γ antagonist. Conclusion In rabbit proximal tubule, PPAR-γ-dependent phosphorylation of ERK mediates pioglitazone-induced reabsorption of Na ~ + and HCO_3 ~ in renal proximal tubules.