Increased responsiveness to JNK1/2 mediates the enhanced H2O2-induced stimulation of Cl−/HCO3− exchanger activity in immortalized renal proximal tubular epithelial cells from the SHR

Abstract

. Increased responsiveness to JNK1/2 mediates the enhanced HO-induced stimulation of Cl/HCO exchanger activity in immortalized renal proximal tubular epithelial cells from the SHR. Biochemical Pharmacology, Elsevier, 2010, 80 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

H2O2 stimulates Cl−/HCO 3− exchanger activity through oxidation of thiol groups in immortalized SHR renal proximal tubular epithelial cells

“…Similar to that previously reported for H 2 O 2 [Simao et al, 2008a;Simao et al, 2010], in the present study SHR PTE cells were also found to have an enhanced sensitivity to DTDP-induce stimulation of Cl [Ying et al, 2007]. In the current study we also found that DTDP treatment increased the affinity of the transporter for HCO In the present study, a lower content of free thiol groups was detected, i.e., cysteine residues in the reduced form, in SHR than in WKY PTE cells.…”

“…In the current study we also found that DTDP treatment increased the affinity of the transporter for HCO In the present study, a lower content of free thiol groups was detected, i.e., cysteine residues in the reduced form, in SHR than in WKY PTE cells. This correlates well with previous data that SHR PTE cells have increased levels of H 2 O 2 production due to an imbalance between oxidant and antioxidant enzymes [Simao et al, 2008a;Simao et al, 2008b;Simao et al, 2010]. As a result, the thiol groups of proteins in SHR cells would be mostly in the oxidized form (and less in the ''free'' form).…”

“…Cysteine residues of proteins are especially susceptible to ROS attack and, given the important role that disulfides play in protein structure and stability, alterations of reactive cysteine thiol groups may change protein function and modulate enzyme activity. In the present study the effects of H 2 O 2 were mimicked by DTDP, i.e., stimulated in a concentration-dependent manner the Cl À /HCO À 3 exchanger activity in WKY and SHR PTE cells [Simao et al, 2008a;Simao et al, 2010]. In contrast, thimerosal had no effect on Cl À /HCO À 3 exchanger activity in both cell lines.…”

“…We have recently shown that SHR PTE cells display enhanced sensitivity to H 2 O 2 -induced stimulation of Cl À /HCO À 3 exchanger activity and that this effect is regulated, at least in part, by JNK1/2, in contrast to WKY PTE cells [Simao et al, 2008a;Simao et al, 2010]. The present study was designed to determine additional mechanisms responsible for differences between renal PTE cells from hypertensive and normotensive rats on their sensitivity to H 2 O 2 -induced stimulation of Cl …”

“…We have previously shown that spontaneously hypertensive rats [Simao et al, 2008a;Simao et al, 2010], which is the result of increased responsiveness to JNK1/2 [Simao et al, 2010]. In addition to MAPK activation, ROS can also modulate ion transport by several other mechanisms, such as, posttranslational modifications of channel proteins (oxidation of aminoacids residues) [Matalon et al, 2003].…”