Airspace Enlargement With Airway Cell Apoptosis in Klotho Mice: A Model of Aging Lung

Ishii, Masaki; Yamaguchi, Yasuhiro; Yamamoto, Hiroshi; Hanaoka, Yoko; Ouchi, Yasuyoshi

doi:10.1093/gerona/63.12.1289

Cited by 36 publications

(29 citation statements)

References 37 publications

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“…These data are among the earliest KO reported changes. Other 3 week KO studies found increased serum Vitamin D (Yoshida et al 2002; Tsujikawa et al 2003), increased skin wnt reporter activation (Liu et al 2007), and increased lung apoptotic and proliferative indexes (Ishii et al 2008). Since skin and lung do not express KL (Kuro-o et al 1997), these data implicate the importance of shed KL.…”

Section: Discussionmentioning

confidence: 93%

“…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%

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

Laszczyk

Fox

et al. 2017

Neurobiology of Aging

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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.

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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

Laszczyk

Fox

et al. 2017

Neurobiology of Aging

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“…Indeed, one animal displayed a particular phenotype resembling aging, caused by the insertional mutation of the transgene in the promoter region of what will be later identified as the Klotho gene. The homozygous animals for the inserted transgene had a shorter life span and precociously developed pathologies related to aging including osteoporosis (86), hypogonadotropic hypogonadism, arteriosclerosis, skin atrophy, pulmonary emphysema (78, 169), neurodegenerative (5, 146), and auditory syndromes (84, 197). …”

Section: Fgf23 Functionmentioning

confidence: 99%

Regulation and Function of the FGF23/Klotho Endocrine Pathways

Martin

David

Quarles

2012

Physiological Reviews

505

437

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Calcium (Ca2+) and phosphate (PO43−) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca2+ levels by increasing Ca2+ reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)2D] production by the kidney, enhancing Ca2+ and PO43− intestinal absorption and increasing Ca2+ and PO43− efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)2D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)2D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO43− handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.

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“…Mice defective in klotho gene expression develop multiple aginglike phenotypes around 3-4 weeks after birth, including growth retardation, hypogonadotropic hypogonadism, rapid thymus atrophy [33], skin atrophy, sarcopenia, vascular calcification, osteopenia [34], pulmonary emphysema [35][36][37], cognition impairment [38], hearing disturbance [39], and motor neuron degeneration [40], and die around 2 months of age. In contrast, transgenic mice that overexpress Klotho live longer than wild-type mice [41].…”

Section: Klothomentioning

confidence: 99%

Overview of the FGF23-Klotho axis

2009

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Recent studies have identified a novel bone-kidney endocrine axis that maintains phosphate homeostasis. When phosphate is in excess, fibroblast growth factor-23 (FGF23) is secreted from bone and acts on the kidney to promote phosphate excretion into urine and suppress vitamin D synthesis, thereby inducing negative phosphate balance. One critical feature of FGF23 is that it requires Klotho, a single-pass transmembrane protein expressed in renal tubules, as an obligate coreceptor to bind and activate FGF receptors. Several hereditary disorders that exhibit inappropriately high serum FGF23 levels are associated with phosphate wasting and impaired bone mineralization. In contrast, defects in either FGF23 or Klotho are associated with phosphate retention and a premature-aging syndrome. The aging-like phenotypes in Klotho-deficient or FGF23-deficient mice can be rescued by resolving hyperphosphatemia with dietary or genetic manipulation, suggesting a novel concept that phosphate retention accelerates aging. Phosphate retention is universally observed in patients with chronic kidney disease (CKD) and identified as a potent risk of death in epidemiological studies. Thus, the bone-kidney endocrine axis mediated by FGF23 and Klotho has emerged as a novel target of therapeutic interventions in CKD.

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Airspace Enlargement With Airway Cell Apoptosis in Klotho Mice: A Model of Aging Lung

Cited by 36 publications

References 37 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

Regulation and Function of the FGF23/Klotho Endocrine Pathways

Overview of the FGF23-Klotho axis

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