Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells

Ikushima, Masashi; Rakugi, Hiromi; Ishikawa, Kazuhiko; Maekawa, Yoshihiro; Yamamoto, Kōichi; Ohta, Junsuke; Chihara, Yukana; Kida, Iwao; Ogihara, Toshio

doi:10.1016/j.bbrc.2005.11.094

Cited by 199 publications

(160 citation statements)

References 27 publications

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“…RNAi with KLB in MRC-5 human primary fibroblasts results in premature senescence with a concomitant up-regulation of p21 (16). Human vascular endothelial cells exposed to recombinant soluble Klotho are resistant to the senescence induced by hydrogen peroxide or etoposide (17). Neither p21 nor p53 levels were increased in immortalized HCEC1-hTERT-shKLG or HCEC1-hTERT-FGF19 cells (data not shown), consistent with the overexpression of KLB that we observed.…”

Section: Discussionsupporting

confidence: 78%

Short Hairpin RNA Screen Indicates That Klotho Beta/FGF19 Protein Overcomes Stasis in Human Colonic Epithelial Cells

Kim

Eskiocak

Stadler

et al. 2011

Journal of Biological Chemistry

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Normal human colonic epithelial cells (HCECs) are not immortalized by telomerase alone but also require CDK4. Some human cell types growth-arrest due to stress-or aberrant signaling-induced senescence (stasis). Stasis represents the consequences of growth conditions culture that are inadequate to maintain long-term proliferation. Overexpressed CDK4 titers out p16 and allows cells to ignore the growth arrest signals produced by stasis. To identify factors contributing to the inadequate culture environment, we used a 62,000-member shRNA library to knock down factors cooperating with human telomerase reverse transcriptase (hTERT) in the immortalization of HCECs. Knockdown of Klotho gamma (KLG; also known as KLPH and LCTL) allowed hTERT to immortalize HCECs. KLG is one isoform of the Klotho family of factors that coordinate interaction between different FGF ligands and the FGF receptor. We also found that knockdown of KLG induced another member of the Klotho family, Klotho beta (KLB). Induction of KLB was maintained and could activate ERK1/2 in immortalized cells. Supplementation of the culture medium with the KLB ligand FGF19 had a similar effect on hTERT-expressing HCECs as knockdown of KLG regarding both immortalization and down-regulation of the tumor suppressor Klotho alpha. Together, these data suggest that KLB is an important regulator in the immortalization of HCECs by facilitating FGF19 growth factor signaling.Human somatic cells have a limited replicative life span in vitro, known as the Hayflick limit (1). Our laboratory has proposed a two-stage model of cellular senescence. Normal human fibroblasts undergo a limited number of divisions in culture and eventually enter a non-dividing state designated replicative senescence or mortality stage 1 because telomeres have shortened enough to induce a DNA damage signal. In the absence of cell cycle check points (e.g. p53 or p16/Rb), cells can continue to divide until extreme telomere shortening initiates a second block to cell division, mortality stage 2 (2). During mortality stage 2 (crisis), end fusions and chromosome breakage cycles result in cell death. The expression of telomerase at levels sufficient to maintain or elongate telomeres can prevent the telomere shortening responsible for both mortality stages 1 and 2 and results in the immortalization of some cell types such as retinal pigment epithelial cells and foreskin fibroblasts (3, 4). However, other cell types growth-arrest due to inadequate culture conditions (lack of growth factors, micronutrients, or cellcell interactions), termed stasis (stress-or aberrant signalinginduced senescence) (5). This telomere length-independent growth arrest can be bypassed either by adjusting the culture conditions to the needs of the particular cell type or by abrogating the stress-induced check point that triggers growth arrest. WI-38 fetal lung fibroblasts cannot be immortalized by ectopic human telomerase reverse transcriptase (hTERT) 2 under standard conditions but are immortalized in low oxygen with media suppleme...

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Section: Discussionsupporting

confidence: 78%

Short Hairpin RNA Screen Indicates That Klotho Beta/FGF19 Protein Overcomes Stasis in Human Colonic Epithelial Cells

Kim

Eskiocak

Stadler

et al. 2011

Journal of Biological Chemistry

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“…We are the first to show that soluble klotho attenuates AngII‐induced senescence in HASMC mediated by Nrf2 as knock‐down of Nrf2 attenuated the protective effect of klotho. Protection against hydrogen peroxide‐mediated senescence by klotho has been previously reported in human fibroblasts and umbilical vein endothelial cells but the role of Nrf2 was not assessed 49, 50, 51.…”

Section: Discussionmentioning

confidence: 98%

The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells

Maltese

Psefteli

Rizzo

et al. 2016

J Cellular Molecular Medi

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Vascular ageing in conditions such as atherosclerosis, diabetes and chronic kidney disease, is associated with the activation of the renin angiotensin system (RAS) and diminished expression of antioxidant defences mediated by the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2). The anti‐ageing hormone klotho promotes longevity and protects against cardiovascular and renal diseases. Klotho has been shown to activate Nrf2 and attenuate oxidative damage in neuronal cells, however, the mechanisms by which it protects against vascular smooth muscle cell VSMC dysfunction elicited by Angiotensin II (AngII) remain to be elucidated. AngII contributes to vascular ageing and atherogenesis by enhancing VSMC oxidative stress, senescence and apoptosis. This study demonstrates that soluble klotho (1 nM, 24 hrs) significantly induces expression of Nrf2 and the antioxidant enzymes haeme oxygenase (HO‐1) and peroxiredoxin‐1 (Prx‐1) and enhances glutathione levels in human aortic smooth muscle cells (HASMC). Silencing of Nrf2 attenuated the induction of HO‐1 and Prx‐1 expression by soluble klotho. Furthermore, soluble klotho protected against AngII‐mediated HASMC apoptosis and senescence via activation of Nrf2. Thus, our findings highlight a novel Nrf2‐mediated mechanism underlying the protective actions of soluble klotho in HAMSC. Targeting klotho may thus represent a therapeutic strategy against VSMC dysfunction and cardiovascular ageing.

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“…These results suggest that klotho regulates cell senescence by suppressing the p53/p21 pathway. Ikushima et al [95] demonstrated that purified recombinant klotho protein could attenuate apoptosis and senescence in human umbilical vein endothelial cells. The same group went on to show that this occurred via mitogenactivated kinase and extracellular signalrelated kinase pathways [96] .…”

Section: Klothomentioning

confidence: 99%

Aging and uremia: Is there cellular and molecular crossover?

White

Yaqoob

Harwood

2015

WJN

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immune systems. However, whilst much has been documented about the shared physical characteristics of aging and uremia, the molecular and cellular similarities between the two have received less attention. In order to bridge this perceived gap we have reviewed published research concerning the common molecular processes seen in aging subjects and CKD patients, with specific attention to altered proteostasis, mitochondrial dysfunction, post-translational protein modification, and senescence and telomere attrition. We have also sought to illustrate how the cell death and survival pathways apoptosis, necroptosis and autophagy are closely interrelated, and how an understanding of these overlapping pathways is helpful in order to appreciate the shared molecular basis behind the pathophysiology of aging and uremia. This analysis revealed many common molecular characteristics and showed similar patterns of cellular dysfunction. We conclude that the accelerated aging seen in patients with CKD is underpinned at the molecular level, and that a greater understanding of these molecular processes might eventually lead to new much needed therapeutic strategies of benefit to patients with renal disease. AbstractMany observers have noted that the morphological changes that occur in chronic kidney disease (CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and rates of frailty in the two groups, and shared characteristics at a pathophysiological level especially in respect to the changes seen in their vascular and REVIEW

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Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells

Cited by 199 publications

References 27 publications

Short Hairpin RNA Screen Indicates That Klotho Beta/FGF19 Protein Overcomes Stasis in Human Colonic Epithelial Cells

Short Hairpin RNA Screen Indicates That Klotho Beta/FGF19 Protein Overcomes Stasis in Human Colonic Epithelial Cells

The anti‐ageing hormone klotho induces Nrf2‐mediated antioxidant defences in human aortic smooth muscle cells

Aging and uremia: Is there cellular and molecular crossover?

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