Effect of EGF on H2O2-induced inhibition of α-MG uptake in renal proximal tubule cells: Involvement of MAPK and AA release

✍ Scribed by Ho Jae Han; Yun Jung Lee; Ji Yong Park; Eun Jung Kim; Jang Hern Lee; Mary L. Taub

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 287 KB
• Volume: 203
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.20214

✦ Synopsis

Abstract

Both oxidative stress and epidermal growth factor (EGF) contribute to the initiation and progression of renal proximal tubular dysfunction under pathophysiologic conditions. Thus, this study was performed (1) to examine both the individual, and the combined effects of H~2~O~2~ and EGF on α‐methyl‐D‐glucopyranoside uptake (α‐MG uptake) in the primary cultured renal proximal tubule cells (PTCs), and (2) to elucidate the involvement of p44/42 mitogen activated protein kinase (MAPK) and phospholipase A~2~ in mediating these actions. Both H~2~O~2~ and EGF inhibited α‐MG uptake individually, while the combination of H~2~O~2~ and EGF further potentiated the inhibitory effect on α‐MG uptake, which was elicited by each agent. H~2~O~2~ not only caused a rapid increase in the phosphorylation of p44/42 MAPK, but also promoted the translocation of cytosolic phospholipase A~2~ (cPLA~2~) from the cytosolic to particulate fraction, and stimulated cellular [^3^H]‐arachidonic acid (AA) release. EGF similarly activates phosphorylation of p44/42 MAPK and stimulates [^3^H]‐AA release. When PTCs were exposed to 100 μM H~2~O~2~ and 50 ng/ml EGF simultaneously, a further increase in the phosphorylation of p44/42 MAPK, of [^3^H]‐AA release, and of prostaglandin E~2~ (PGE~2~) production was elicited as compared with the effects of each individual agonist alone. Moreover, the additive phosphorylation of p44/42 MAPK, [^3^H]‐AA release, and PGE~2~ production by H~2~O~2~ and EGF was almost completely inhibited by the p44/42 MAPK inhibitor, PD 98059. In conclusion, these results are consistent with the hypothesis that under conditions of oxidative stress, the H~2~O~2~‐induced inhibition of α‐MG uptake in the renal proximal tubule is mediated through a modulation of the EGF signaling pathway, promoting further phosphorylation of p44/42 MAPK, activation of PLA~2~. © 2004 Wiley‐Liss, Inc.