Klotho Ameliorates Chemically Induced Endoplasmic Reticulum (ER) Stress Signaling

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.

The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System

“…Klotho was found down-regulated in PC12 cells exposed to glutamate (55) and in hippocampal samples from epilepsy patients (56). Other reports suggested the important role of Klotho in the regulation of endoplasmic reticulum stress in SH-SY5Y cells (57) and in the neuroprotective effect of a plant antioxidant, ligustilide, in an AD mouse model (45). In addition, Klotho concentrations were found to be lower in CSF of patients with AD when compared with age-matched controls (58).…”

Klotho Gene and Selective Serotonin Reuptake Inhibitors: Response to Treatment in Late-Life Major Depressive Disorder

“…Klotho protein ameliorates chemically induced ER stress signaling [26], and Klotho gene (KL) may be a potential translational target in ER stress in MDD. Klotho-deficient mice showed an increased overall burden of CNS oxidative stress [27], suggesting that this protein may exert brain-wide antioxidative and anti-inflammatory effects [28,29].…”

The relevance of α-KLOTHO to the central nervous system: Some key questions

“…These include resistance to oxidative and endoplasmic reticulum stresses, and protection from cytotoxicity elicited by the Alzheimer's disease protein Aβ and glutamate excitotoxicity (Cheng et al, 2015;Zeldich et al, 2014). A number of cell signaling pathways have been reported as modulated by α-Klotho and suggested to underlie these observations, including the PI3K/Akt, ASK1/p38 MAPK and PERK pathways (Banerjee et al, 2013;Brobey et al, 2015;Zeldich et al, 2014). Experiments by Xin and colleagues, showed α-Klotho participation in oxidative stress resistance in cortical neurons and cerebellar granule cells.…”