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Molecular Cloning of RatklothocDNA: Markedly Decreased Expression ofklothoby Acute Inflammatory Stress

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Abstract

We have recently identified a novel gene, termedklotho,that is involved in the suppression of several aging phenotypes. The gene encodes a membrane protein that shares sequence similarity with the β-glucosidases of bacteria and plants. In this study, we isolated ratklothocDNA and examined its tissue distribution in rats. The deduced amino acid sequence of rat Klotho protein was 1014 amino acids in length and 94 and 85% homologous to those of mouse and human Klotho proteins, respectively. Northern blot analysis using the ratklothocDNA probe identified a single transcript of 5.2 kb in size expressed predominantly in the kidney, while RT-PCR detected low levels of expression also in the brain, lung, intestine, and ovaries. During development,klothoexpression in the kidney was markedly augmented after birth. Chromosomal localization of ratklothowas mapped to 12q12. Northern blot analysis showed that expression ofklothowas markedly decreased by lipopolysaccharide (LPS)in vivo,suggesting that expression ofklothois affected by acute inflammatory stress. The present study leads to a better understanding of the physiologic and pathophysiologic roles of Klotho.

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    In rats, serum sKlotho levels was significantly higher (P < 0.05) in fluoride-exposed groups than that in the control group (Fig. 2). As Klotho can be expressed in the kidney and small intestine (Ohyama et al., 1998), which serves as the major source of sKlotho, the expression of Klotho protein in the kidney and small intestine of rats treated with different doses of NaF was measured. Immunohistochemistry results showed that the Klotho expression in the kidney and small intestine increased with increased doses of NaF treatment (Fig. 3).

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Abbreviations used: FISH, fluorescencein situhybridization; LPS, lipopolysaccharide; L-NAME,Nω-nitro-L-arginine methyl ester; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RT-PCR, reverse transcription-polymerase chain reaction; RPTEC, human renal proximal tubular epithelial cells; 293 cells, Human embryonic kidney 293 cells; TGF-β, transforming growth factor-β

1

To whom correspondence should be addressed at Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-22, Showa, Maebashi, Gunma 371-8511, Japan. Fax: 81-27-220-8150. E-mail:[email protected].

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