早老素PS1/PS2双敲除小鼠中klotho表达的下降和血磷的升高

摘要/Abstract

摘要： 为了探讨抗衰老基因klotho是否参与早老素presenilin 1/presenilin 2条件性双敲除（PS cDKO）小鼠的衰老症状，分析了PS cDKO小鼠中肾脏和大脑中klotho的表达.结果发现，与同龄正常对照小鼠相比，12月龄雌性PS cDKO小鼠中肾脏klotho表达明显下降，血磷水平明显升高，而血钙略微下调，但同时几乎没有观察到肾功能障碍；而在大脑中，早在3月龄时klotho水平就已发生下降.这些结果说明klotho可能与PS cDKO小鼠的症状有关，其表达水平的下降可能导致了血磷浓度的上升，但不足以引发肾功能障碍.此外，klotho作为一个抗氧化和抗炎症的因子，其表达下降可能与PS cDKO小鼠体内氧化压力和炎症反应的升高有关.

关键词: klotho, PS cDKO小鼠, 磷, 钙, 衰老

Abstract: In this study, we investigated the expression of klotho, an anti-aging gene, and its involvement of premature aging phenotypes of presenilin 1/presenilin 2 conditional double knockout (PS cDKO) mice. The results showed that renal klotho level was significantly decreased in 12-month-old female PS cDKO mice when compared with control mice. Meanwhile, significant elevations of plasma phosphorus but slight reduction of calcium and almost no sign of renal dysfunction were observed. In PS cDKO brains, down-regulated klotho level was observed as early as 3 months of age. These findings indicate a possible role of klotho in the disorders of PS cDKO mice. The declined klotho expression may be responsible for the excess blood phosphate, but it seems that such a moderate decline in klotho level and impaired phosphate metabolism were not sufficient to elicit renal dysfunction in PS cDKO mice. However, as klotho is an anti-oxidative and anti-inflammation factor, klotho decline may contribute to the increased oxidative stress and inflammation in PS cDKO mice.

Key words: klotho, PS cDKO mice, phosphate, calcium, aging

中图分类号:

Q786

王栋，翟文珠，苏静静，孟博，赵政，胡金锋. 早老素PS1/PS2双敲除小鼠中klotho表达的下降和血磷的升高[J]. 华东师范大学学报(自然科学版), 2013, 2013(2): 75-83, 91.

WANG Dong， ZHAI Wen-zhu， SU Jing-jing， MENG Bo，ZHAO Zheng， HU Jin-feng. Decreased klotho expression and elevated blood phosphate level in presenilin PS1/PS2 conditional double knockout mice[J]. Journal of East China Normal University(Natural Sc, 2013, 2013(2): 75-83, 91.

参考文献

［1］ KURO-O M, MATSUMURA Y, AIZAWA H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing［J］. Nature, 1997, 390(6655): 45-51.

［2］ NAGAI T, YAMADA K, KIM H C, et al. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress ［J］. Faseb J, 2003, 17(1): 50-52.

［3］ SHIOZAKI M, YOSHIMURA K, SHIBATA M, et al. Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice［J］. Neuroscience, 2008, 152(4): 924-941.

［4］ KUROSU H, YAMAMOTO M, CLARK J D, et al. Suppression of aging in mice by the hormone klotho［J］. Science, 2005, 309(5742): 1829-1833.

［5］ MATSUMURA Y, AIZAWA H, SHIRAKI-IIDA T, et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein［J］. Biochemical and Biophysical Research Communications, 1998, 242(3): 626-630.

［6］ SHIRAKI-IIDA T, AIZAWA H, MATSUMURA Y, et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein［J］. FEBS Letters, 1998, 424(1-2): 6-10.

［7］ URAKAWA I, YAMAZAKI Y, SHIMADA T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23［J］. Nature, 2006, 444(7120): 770-774.

［8］ CHANG Q, HOEFS S, VAN DER KEMP A W, et al. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel［J］. Science, 2005, 310(5747): 490-493.

［9］ CHA S K, ORTEGA B, KUROSU H, et al. Removal of sialic acid involving klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1［J］. Proc Natl Acad Sci USA, 2008, 105(28): 9805-9810.

［10］ IMURA A, TSUJI Y, MURATA M, et al. alpha-Klotho as a regulator of calcium homeostasis［J］. Science, 2007, 316(5831): 1615-1618.

［11］ YAMAMOTO M, CLARK J D, PASTOR J V, et al. Regulation of oxidative stress by the anti-aging hormone klotho［J］. Journal of Biological Chemistry, 2005, 280(45): 38029-38034.

［12］ MAEKAWA Y, ISHIKAWA K, YASUDA O, et al. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation［J］. Endocrine, 2009, 35(3): 341-346.

［13］ LIU F, WU S, REN H, et al. Klotho suppresses RIG-I-mediated senescence-associated inflammation［J］. Nature Cell Biology, 2011, 13(3): 254-262.

［14］ MORENO J A, IZQUIERDO M C, SANCHEZ-NINO M D, et al. The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB［J］. Journal of the American Society of Nephrology, 2011, 22(7): 1315-1325.

［15］ ZHAO Y, BANERJEE S, DEY N, et al. Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation［J］. Diabetes, 2011, 60(7): 1907-1916.

［16］ FENG R, WANG H, WANG J, et al. Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer’s presenilin-1 and presenilin-2［J］. Proc Natl Acad Sci USA, 2004, 101(21): 8162-8167.

［17］ SAURA C A, CHOI S Y, BEGLOPOULOS V, et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration［J］. Neuron, 2004, 42(1): 23-36.

［18］ BEGLOPOULOS V, SUN X, SAURA C A, et al. Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice［J］. Journal of Biological Chemistry, 2004, 279(45): 46907-46914.

［19］ JIANG X, ZHANG D, SHI J, et al. Increased inflammatory response both in brain and in periphery in presenilin 1 and presenilin 2 conditional double knock-out mice［J］. Journal of Alzheimers Disease, 2009, 18(3): 515-523.

［20］ ZHU M, GU F, SHI J, et al. Increased oxidative stress and astrogliosis responses in conditional double-knockout mice of Alzheimer-like presenilin-1 and presenilin-2［J］. Free Radical Biology and Medicine, 2008, 45(10): 1493-1499.

［21］ WANG D, YANG L, SU J, et al. Attenuation of neurodegenerative phenotypes in Alzheimer-like presenilin 1/presenilin 2 conditional double knockout mice by EUK1001, a promising derivative of xanomeline［J］. Biochemical and Biophysical Research Communications, 2011, 410(2): 229-234.

［22］ DUCE J A, PODVIN S, HOLLANDER W, et al. Gene profile analysis implicates klotho as an important contributor to aging changes in brain white matter of the rhesus monkey［J］. Glia, 2008, 56(1): 106-117.

［23］ YAMAZAKI Y, IMURA A, URAKAWA I, et al. Establishment of sandwich ELISA for soluble alpha-klotho measurement: Age-dependent change of soluble alpha-klotho levels in healthy subjects［J］. Biochemical and Biophysical Research Communications, 2010, 398(3): 513-518.

［24］ KOH N, FUJIMORI T, NISHIGUCHI S, et al. Severely reduced production of klotho in human chronic renal failure kidney［J］. Biochemical and Biophysical Research Communications, 2001, 280(4): 1015-1020.

［25］ HU M C, KURO-O M, MOE O W. Secreted klotho and chronic kidney disease［J］. Advances in Experimental Medicine and Biology, 2012, 728: 126-157.

［26］ SUGIURA H, YOSHIDA T, TSUCHIYA K, et al. Klotho reduces apoptosis in experimental ischaemic acute renal failure［J］. Nephrology Dialysis Transplantation, 2005, 20(12): 2636-2645.

［27］ KOSAKAI A, ITO D, NIHEI Y, et al. Degeneration of mesencephalic dopaminergic neurons in klotho mouse related to vitamin D exposure［J］. Brain Research, 2011, 1382: 109-117.

［28］ LI H, WANG B, WANG Z, et al. Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP［J］. Proc Natl Acad Sci USA, 2010, 107(40): 17362-17367.

［29］〖JP+3〗WU P, SHEN Q, DONG S, et al. Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice［J］. Neurobiology of Aging, 2008, 29(10): 1502-1511.〖JP〗

［30］ DONG S, LI C, WU P, et al. Environment enrichment rescues the neurodegenerative phenotypes in presenilins-deficient mice［J］. European Journal of Neuroscience, 2007, 26(1): 101-112.

［31］ BERNDT T, KUMAR R. Phosphatonins and the regulation of phosphate homeostasis［J］. Annual Review of Physiology, 2007, 69: 341-359.

［32］ KUROSU H, OGAWA Y, MIYOSHI M, et al. Regulation of fibroblast growth factor-23 signaling by klotho［J］. Journal of Biological Chemistry, 2006, 281(10): 6120-6123.

［33］ TSUJIKAWA H, KUROTAKI Y,FUJIMORI T, et al. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system［J］. Molecular Endocrinology, 2003, 17(12): 2393-2403.
［34］ BROWNSTEIN C A, ADLER F, NELSON-WILLIAMS C, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism［J］. Proc Natl Acad Sci USA, 2008, 105(9): 3455-3460.

［35］ KESTENBAUM B, SAMPSON J N, RUDSER K D, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease［J］. Journal of the American Society of Nephrology, 2005, 16(2): 520-528.

［36］ RAKUGI H, MATSUKAWA N, ISHIKAWA K, et al. Anti-oxidative effect of klotho on endothelial cells through cAMP activation［J］. Endocrine, 2007, 31(1): 82-87.

［37］ GU F, ZHU M, SHI J, et al. Enhanced oxidative stress is an early event during development of Alzheimer-like pathologies in presenilin conditional knock-out mice［J］. Neuroscience Letters, 2008, 440(1): 44-48.

［38］ HERREMAN A, HARTMANN D, ANNAERT D, et al. Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency［J］. Proc Natl Acad Sci USA, 1999, 96(21): 11872-11877.

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