Mechanism On The Treatment Of Autosomal Polycystic Kidney Disease With Roglitazone: Role Of ERK1/2 Signal Pathway

Aim:Mechanism on theTreatment of Autosomal Polycystic Kidney Disease with Roglitazone: Role of ERK1/2 Signal Pathway Methods Alterations in expression levels and phosphorylations of ERK and PPAR-γunder the effect of roglitazone on MDCK cells were analyzed by Western blotting, and mechanism of action of the effect of roglitazone on MDCK cells and therefore affect ERK signal transduction pathway was investigated. Production of reactive oxygen species (ROS) was detected by flow cytometry using dichlorofluorescein (DCF). Expression levels and phosphorylations of ERK1/2 and EGFR during treating intervened ADPKD animal model Han-SPRD rats with roglitazone and TKI were detected by immunohistochemistry assay and Western blotting, respectively. Results:It's revealed that, within a short period of time after roglitazone started to act on MDCK cells, ERK was activated and phosphorylation of ERK was increased. Activation of ERK may be suppressed by Src activity inhibitor, TKI inhibitor or MEK inhibitor, but may not be blocked by of PPAR-γreceptor inhibitor. However, 24 hrs after roglitazone started to act, apparent inhibition of ERK1/2 phosphorylation was also observed, and the inhibition was dose-dependent. Treating of intervened ADPKD animal model Han-SPRD rats with roglitazone and TKI showed that tissue ERK activity may be inhibited, while expression of ERK remained unchanged and phosphorylation activity and expression level of EGFR expression were decreased. Conclusion: Within MDCK cells, effect of roglitazone on ERK1 signal pathway is acting time-related and bidirectional. While mechanism of transitory activation of ERK1/2 was related to intracellular production of ROS, and also associated with Src. EGFR and MEK, long-term intracellular effect of roglitazone was to inhibit activation of ERK, the application of the combination of roglitazone and TKI PD153035 suppressed ERK activity more efficiently.