Disruption of the<i>klotho</i>Gene Causes Pulmonary Emphysema in Mice

Suga, Tatsuo; Kurabayashi, Masahiko; Sando, Yoshichika; Ohyama, Yoshio; Maeno, Toshitaka; Maeno, Yoshiharu; Aizawa, Hiroki; Matsumura, Yutaka; Kuwaki, Tomoyuki; Kuro‐o, Makoto; Nabeshima, Yo Ichi; Nagai, Ryozo

doi:10.1165/ajrcmb.22.1.3554

Cited by 155 publications

(37 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…KL HET mice show decreased freezing consistent with cognitive impairment 24 hours after training, although impairment was less pronounced than KO mice (Figure 6C). Although KL heterozygotes do not develop the severe symptoms of loss of KL from renal systems (Kuro-o et al 1997), they do display lung and heart abnormalities most likely resulting from decreased shed KL (Suga et al 2000; Sato et al 2005; Ishii et al 2008). Meanwhile, consistent with the previous report (Dubal et al 2014), 6 month OE mice froze more than WT (Figure 6D).…”

Section: Resultsmentioning

confidence: 99%

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

Laszczyk

Fox

et al. 2017

Neurobiology of Aging

View full text Add to dashboard Cite

Although the absence of the age-regulating klotho protein causes klotho-deficient mice to rapidly develop cognitive impairment and increasing klotho enhances hippocampal-dependent memory, the cellular effects of klotho that mediate hippocampal-dependent memory function are unknown. Here we show premature aging of the klotho-deficient hippocampal neurogenic niche as evidenced by reduced numbers of neural stem cells, decreased proliferation, and impaired maturation of immature neurons. Klotho-deficient neurospheres show reduced proliferation and size that is rescued by supplementation with shed klotho protein. Conversely, 6 month old klotho overexpressing mice exhibit increased numbers of neural stem cells, increased proliferation, and more immature neurons with enhanced dendritic arborization. Protection from normal age-related loss of object location memory with klotho overexpression and loss of spatial memory when klotho is reduced by even half suggest direct, local effects of the protein. Together these data show that klotho is a novel regulator of postnatal neurogenesis affecting neural stem cell proliferation and maturation sufficient to impact hippocampal-dependent spatial memory function.

show abstract

Section: Resultsmentioning

confidence: 99%

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

Laszczyk

Fox

et al. 2017

Neurobiology of Aging

View full text Add to dashboard Cite

show abstract

“…Recombinant klotho, a single-transmembrane protein that exists in a membrane bound and soluble form and acts as a FGF23 co-receptor, protects the alveolar epithelium against oxidative damage (11-13). Furthermore, mice lacking klotho develop an aging phenotype with widened alveolar spaces, consistent with pulmonary emphysema (14). …”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor 23 and Klotho contribute to airway inflammation

et al. 2018

View full text Add to dashboard Cite

Circulating levels of fibroblast growth factor (FGF) 23 are associated with systemic inflammation and increased mortality in chronic kidney disease. α-klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and klotho-mediated FGFR activation delineates a pathophysiologic mechanism in COPD remains unclear. We hypothesized that FGF23 can potentiate airway inflammation via klotho independent FGFR4 activation. FGF23 and its effect were studied using plasma and transbronchial biopsies from COPD and control patients and primary human bronchial epithelial cells isolated from COPD patients as well as a murine COPD model. Plasma FGF23 levels were significantly elevated in COPD patients. Exposure of airway epithelial cells to cigarette smoke and FGF23 led to a significant increase in IL-1β release via klotho-independent FGFR4-mediated activation of phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling. In addition, klotho knockout mice developed COPD and showed airway inflammation and elevated FGFR4 expression in their lungs, whereas overexpression of klotho led to an attenuation of airway inflammation. In conclusion, cigarette smoke induces airway inflammation by downregulation of klotho and activation of FGFR4 in the airway epithelium in COPD. Inhibition of FGF23 or FGFR4 might serve as a novel anti-inflammatory strategy in COPD.

show abstract

“…The purpose of the present study is to examine histologically whether the shape and size distributions of air spaces in the lungs have fractal properties and to investigate the differences between emphysematous lungs and controls, by using a mouse model of emphysema called the klotho mouse (13). klotho-null mutants (kl Ϫ/Ϫ ) were established by targeted gene disruption and reveal the same phenotype as the original klotho mice (14).…”

mentioning

confidence: 99%

“…and obvious emphysema after milk feeding (15). The first histological changes in the lung of the original klotho mice appear at 4 weeks of age with both destruction of alveolar walls and air space enlargement (13). Recently, the abnormal activation of vitamin D was reported to be the major cause of the phenotype of the klotho mice (14).…”

mentioning

confidence: 99%

Morphological mechanism of the development of pulmonary emphysema in klotho mice

Sato¹,

Hirai²,

Imura

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The concept of fractal geometry is useful for the analysis of irregular and complex structures often seen in nature. Here we apply this concept to investigate the structural mechanism of the development of pulmonary emphysema in the klotho mouse, which, after milk feeding, exhibits characteristics resembling aging and develops emphysema. We calculated the relationships between perimeter and size characterizing shape and between cumulative frequency and size of the terminal air spaces identified from histologic slides and found that both relations followed a power law with fractal properties. However, the fractal dimensions related to the shape and size (Dsn) in the klotho mice were significantly lower than in controls. Additionally, in the klotho mice, Dsn decreased with age without significant change in mean linear intercept. These abnormal morphological changes were restored when the klotho mice were fed with a vitamin D-deficient diet. Previously undescribed morphological model simulations showed that a random destruction, in which the destruction process occurs homogeneously in the lungs, was more consistent with the data than a correlated destruction that is usually seen in smoking-related human emphysema. These results suggest that the pathological changes in the lungs of the klotho mice are derived not from localized causes, but from systemic causes that are related to abnormal activation of vitamin D. The morphogenesis of emphysema in the klotho mice and morphological analyses using fractal geometry may contribute to the understanding of the progressive nature and cause of parenchymal destruction in human emphysema.chronic obstructive pulmonary disease ͉ fractal ͉ lung ͉ morphometry ͉ simulation C hronic obstructive pulmonary disease (COPD) is a progressive lung disease that consists of airway obstruction and pulmonary emphysema, which is characterized pathologically by abnormal and permanent enlargement of the air spaces distal to the terminal bronchioles with the destruction of their walls (1). To study the mechanism of progression, several techniques have been proposed to evaluate air space enlargement and parenchymal destruction in various mouse models of emphysema. The enlargement of air spaces has been evaluated by using the mean linear intercept (Lm) technique, described originally by Dunnill (2). The degree of parenchymal destruction is usually determined by a microscopic point counting technique called the Destructive Index (DI) (3). These morphological indexes have proved useful in evaluating the extent and severity of emphysema, one form of COPD, and have been used for understanding of the relationship between pathological and clinical findings (4, 5). However, these indexes are limited because they do not account for the irregularities and structural complexity of the lung periphery, and hence they are unable to quantify how the air spaces become enlarged and destroyed (6-8).Recently, the concept of fractal geometry developed by Mandelbrot (9) was applied to pulmonary physiology and histology...

show abstract

Disruption of theklothoGene Causes Pulmonary Emphysema in Mice

Cited by 155 publications

References 26 publications

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

Fibroblast growth factor 23 and Klotho contribute to airway inflammation

Morphological mechanism of the development of pulmonary emphysema in klotho mice

Contact Info

Product

Resources

About