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Cell Physiol Biochem. 2013;31(4-5):659-72. doi: 10.1159/000350085. Epub 2013 May 8.

Klotho ameliorates chemically induced endoplasmic reticulum (ER) stress signaling.

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1
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-1060, USA.

Abstract

BACKGROUND:

Both endoplasmic reticulum (ER) stress, a fundamental cell response associated with stress-initiated unfolded protein response (UPR), and loss of Klotho, an anti-aging hormone linked to NF-κB-induced inflammation, occur in chronic metabolic diseases such as obesity and type 2 diabetes. We investigated if the loss of Klotho is causally linked to increased ER stress.

METHODS:

We treated human renal epithelial HK-2, alveolar epithelial A549, HEK293, and SH-SH-SY5Y neuroblastoma cells with ER stress-inducing agents, thapsigargin and/or tunicamycin. Effects of overexpression or siRNA-mediated knockdown of Klotho on UPR signaling was investigated by immunoblotting and Real-time PCR.

RESULTS:

Elevated Klotho levels in HK-2 cells decreased expression of ER stress markers phospho--IRE1, XBP-1s, BiP, CHOP, pJNK, and phospho-p38, all of which were elevated in response to tunicamycin and/or thapsigargin. Similar results were observed using A549 cells for XBP-1s, BiP, and CHOP in response to thapsigargin. Conversely, knockdown of Klotho in HEK 293 cells using siRNA caused further thapsigargin-induced increases in pIRE-1, XBP-1s, and BiP. Klotho overexpression in A549 cells blocked thapsigargin-induced caspase and PARP cleavage and improved cell viability.

CONCLUSION:

Our data indicate that Klotho has an important role in regulating ER stress and that loss of Klotho is causally linked to ER stress-induced apoptosis.

PMID:
23711492
DOI:
10.1159/000350085
[Indexed for MEDLINE]
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