Klotho ameliorates chemically induced endoplasmic reticulum (ER) stress signaling

Srijita Banerjee, Yanhua Zhao, Partha S. Sarkar, Kevin P. Rosenblatt, Ronald G. Tilton, Sanjeev Choudhary

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)659-672
Number of pages14
JournalCellular Physiology and Biochemistry
Volume31
Issue number4-5
DOIs
StatePublished - May 2013

Keywords

  • ER stress
  • Klotho
  • Thapsigargin
  • Tunicamycin
  • Unfolded protein response

ASJC Scopus subject areas

  • General Medicine

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