Klotho Protein Activates the PKC Pathway in the Kidney and Testis and Suppresses 25-Hydroxyvitamin D&lt;SUB&gt;3&lt;/SUB&gt; 1α-Hydroxylase Gene Expression

Imai, Michio; Ishikawa, Kazuhiko; Matsukawa, Naomichi; Kida, Iwao; Ohta, Junsuke; Ikushima, Masashi; Chihara, Yukana; Xu, Rui; Rakugi, Hiromi; Ogihara, Toshio

doi:10.1385/endo:25:3:229

Cited by 45 publications

(29 citation statements)

References 24 publications

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“…41 Soluble Klotho has been reported to act directly on the proximal tubules to increase phosphate excretion independent of Fgf23. 16 Moreover, Imai et al 42 reported that soluble Klotho suppresses Cyp27b1 through a pathway independent of cyclic adenosine monophosphate (cAMP) and protein kinase C (PKC). However, no measureable differences in serum soluble Klotho between knockout and wild-type mice were observed in the 2 lines examined (Kap-KL and Slc34a1-KL).…”

Section: Discussionmentioning

confidence: 99%

In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling

Ide

Olauson

Sato

et al. 2016

Kidney International

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Klotho is a transmembrane protein expressed in the renal tubules where it acts as a permissive coreceptor for fibroblast growth factor 23 (FGF23). FGF23 signaling reduces the abundance of CYP27b1 and phosphate cotransporters NPT2a and NPT2c, leading to a decrease in 1,25(OH)2D3 synthesis and a rise in urinary phosphate excretion, respectively. Systemic or whole-nephron deletion of Klotho in mice results in renal FGF23 resistance characterized by high 1,25(OH)2D3 and phosphate levels and premature aging. Expression of Klotho is highest in the distal tubules, whereas 25OH vitamin D 1α hydroxylation and phosphate reabsorption predominantly occur in the proximal tubules. Currently, the segment-specific roles of Klotho in renal tubules are not fully understood. Here we have generated mice with Klotho specifically ablated from the proximal tubules using 3 different Cre mouse strains. All 3 models displayed impaired urinary phosphate excretion and increased abundance of NPT2a in the brush border membrane. Notably, hyperphosphatemia in knockout mice was mild or nonexistent under basal conditions but occurred upon high phosphate loading, indicating the presence of compensatory mechanisms. Effects on 1,25(OH)2D3 varied between mouse strains but were modest overall. Thus, Klotho expressed in the proximal tubules has a defined but limited role in renal phosphate handling in vivo.

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Section: Discussionmentioning

confidence: 99%

In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling

Ide

Olauson

Sato

et al. 2016

Kidney International

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“…Soluble Klotho acts as a humoral factor (72), potentially through an unknown cell-surface Klotho receptor, and as an enzyme (25, 202) regulating several cell surface glycoproteins. Indeed, secreted αKlotho inhibits insulin- and insulin-like growth factor I (IGF-I)-induced autophosphorylation of insulin and IGF-I receptor in vitro (99, 218).…”

Section: Fgf23 Functionmentioning

confidence: 99%

Regulation and Function of the FGF23/Klotho Endocrine Pathways

Martin

David

Quarles

2012

Physiological Reviews

516

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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“…Blots were blocked in 5% nonfat milk in PBS for 1 h; incubated with rat monoclonal anti-Klotho (KM2076), anti-ICAM-1 (Cell Signaling), anti-VCAM-1 (R&D systems), anti-phospho eNOS (Cell signaling), or anti-phospho IjB (Cell Signaling) antibodies for over night; and incubated with peroxidase-conjugated secondary antibodies for 1 h. To monitor equal loading of proteins, membranes were incubated with anti-a-tubulin antibody (Calbiochem, La Jolla, CA). Immunoblots were developed with an ECL plus Western blotting detection system (GE Healthcare, Little Chalfont, Buckinghamshire, UK), as described previously [23,24].…”

Section: Western Blot Analysismentioning

confidence: 99%

Klotho suppresses TNF-α-induced expression of adhesion molecules in the endothelium and attenuates NF-κB activation

Maekawa

Ishikawa

Yasuda

et al. 2009

Endocr

Self Cite

230

161

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Klotho is a senescence suppressor protein that, when overexpressed, extends the lifespan of mice. Klotho-disrupted mice exhibit atherosclerosis and endothelial dysfunction, which led us to investigate the effect of the Klotho protein on vascular inflammation, particularly adhesion molecule expression. In this study, human umbilical vein endothelial cells (HUVECs) were preincubated with Klotho protein and then exposed to tumor necrosis factor-alpha (TNF-alpha) or vehicle. Reverse transcription-PCR and Western blot analyses revealed that Klotho suppressed TNF-alpha-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). NF-kappaB activation, IkappaB phosphorylation induced by TNF-alpha were also attenuated by Klotho protein administration. The inhibition of eNOS phosphorylation by TNF-alpha was reversed by Klotho. Furthermore, Klotho inhibited TNF-alpha-induced monocyte adhesion to HUVECs and suppressed adhesion molecule expression in an organ culture of the rat aorta. These results suggest that Klotho suppresses TNF-alpha-induced expression of adhesion molecules and NF-kappaB activation. Klotho may have a role in the modulation of endothelial inflammation.

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Klotho Protein Activates the PKC Pathway in the Kidney and Testis and Suppresses 25-Hydroxyvitamin D<SUB>3</SUB> 1α-Hydroxylase Gene Expression

Cited by 45 publications

References 24 publications

In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling

In vivo evidence for a limited role of proximal tubular Klotho in renal phosphate handling

Regulation and Function of the FGF23/Klotho Endocrine Pathways

Klotho suppresses TNF-α-induced expression of adhesion molecules in the endothelium and attenuates NF-κB activation

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