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Horm Metab Res 2015; 47(02): 125-132
DOI: 10.1055/s-0034-1375689
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Cerebral Klotho Protein as a Humoral Factor for Maintenance of Baroreflex

L.-J. Chen   *
1   Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
,
M.-F. Cheng   *
2   Division of Nephrology, Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
,
P.-M. Ku
3   Department of Cardiology, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan
,
J.-T. Cheng
1   Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
4   Institute of Medical Sciences, Chang Jung Christian University, Guiren, Tainan City, Taiwan
› Author Affiliations
Further Information

Publication History

received 21 December 2013

accepted 24 April 2014

Publication Date:
27 May 2014 (online)

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Abstract

The klotho protein produced by the choroid plexus is known as a humoral factor in central nervous system. Many hormones affecting the baroreflex sensitivity have been introduced in the brain. However, role of klotho in the baroreflex sensitivity is still unknown. Recently, mutations in the klotho gene have been linked to cardiovascular diseases in both animals and human subjects. Also, silencing of brain klotho has been reported to enhance cold-induced elevation of blood pressure. Thus, we investigated the role of klotho in maintenance of central cardiovascular reflex sensitivity. Male Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were used. Either klotho shRNA or scramble shRNA was also ICV-infused into the brains of WKY rats to investigate the role of klotho in brain. Recombinant klotho or rat IgG was infused into the cerebral paraventricle (ICV) of SHRs for further understanding the role of klotho in hypertension. The baroreflex sensitivity was detected using the challenge with a depressor dose of sodium nitroprusside (SNP, 50 μg/kg) or with a pressor dose of phenylephrine (PE, 8 μg/kg). We found that silencing of klotho expression in the brain decreased the baroreflex sensitivity in WKY rats. Also, modulation of the blood pressure for one week altered the cardiovascular homeostasis and resulted in an increased expression of klotho in medulla oblongata. Moreover, the baroreflex sensitivity was restored in SHRs that received recombinant klotho through ICV brain. Thus, klotho is involved in the maintenance of baroreflex sensitivity in the brain.

Key words

klotho - baroreflex sensitivity - klotho shRNA - SHR - ICV injection

* Contributed equally to this study.


 

  • References

  • 1 Kirchheim HR. Systemic arterial baroreceptor reflexes. Physiol Rev 1976; 56: 100-177
    PubMedSearch in Google Scholar
  • 2 Cisternas JR, Valenti VE, Alves TB, Ferreira C, Petenusso M, Breda JR, Pires AC, Tassi N, de Abreu LC. Cardiac baroreflex is already blunted in eight weeks old spontaneously hypertensive rats. Inter Archiv Med 2010; 3: 2
    PubMedSearch in Google Scholar
  • 3 Song SW, Liu AJ, Bai C, Su BL, Ma XJ, Shen FM, Duan JL, Su DF. Blood pressure reduction combining baroreflex restoration for stroke prevention in hypertension in rats. Front Pharmacol 2010; 1: 6
    PubMedSearch in Google Scholar
  • 4 Saint Martin M, Sforza E, Thomas-Anterion C, Barthelemy JC, Roche F, Group PS. Baroreflex sensitivity, vascular risk factors, and cognitive function in a healthy elderly population: the PROOF cohort. J Am Geriat Soc 2013; 61: 2096-2102
    CrossrefPubMedSearch in Google Scholar
  • 5 Iliescu R, Tudorancea I, Irwin ED, Lohmeier TE. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am J Physiol Heart Circ Physiol 2013; 305: H1080-H1088
    CrossrefPubMedSearch in Google Scholar
  • 6 Guimaraes PS, Santiago NM, Xavier CH, Velloso EP, Fontes MA, Santos RA, Campagnole-Santos MJ. Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats. Am J Physiol Heart Circulat Physiol 2012; 303: H393-H400
    PubMedSearch in Google Scholar
  • 7 Kar S, Gao L, Belatti DA, Curry PL, Zucker IH. Central angiotensin (1-7) enhances baroreflex gain in conscious rabbits with heart failure. Hypertension 2011; 58: 627-634
    CrossrefPubMedSearch in Google Scholar
  • 8 do Carmo JM, Hall JE, da Silva AA. Chronic central leptin infusion restores cardiac sympathetic-vagal balance and baroreflex sensitivity in diabetic rats. Am J Physiol Heart Circul Physiol 2008; 295: H1974-H1981
    CrossrefPubMedSearch in Google Scholar
  • 9 Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390: 45-51
    CrossrefPubMedSearch in Google Scholar
  • 10 Xu C, Song RJ, Yang J, Jiang B, Wang XL, Wu W, Zhang W. Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in Eastern China. Gene 2013; 526: 494-497
    CrossrefPubMedSearch in Google Scholar
  • 11 Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H. A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population. Clin Chim Acta: Inter J Clinical Chem 2010; 411: 386-390
    PubMedSearch in Google Scholar
  • 12 Tangri N, Alam A, Wooten EC, Huggins GS. Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians: a candidate gene study of the Framingham Offspring Cohort. Nephrol Dial Transplant 2011; 26: 3998-4002
    CrossrefPubMedSearch in Google Scholar
  • 13 Zhang F, Zhai G, Kato BS, Hart DJ, Hunter D, Spector TD, Ahmadi KR. Association between KLOTHO gene and hand osteoarthritis in a female Caucasian population. Osteoarthritis Cartilage/OARS 2007; 15: 624-629
    PubMedSearch in Google Scholar
  • 14 Freathy RM, Weedon MN, Melzer D, Shields B, Hitman GA, Walker M, McCarthy MI, Hattersley AT, Frayling TM. The functional “KL-VS” variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians. BMC Med Gen 2006; 7: 51
    PubMedSearch in Google Scholar
  • 15 Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H, Inoue S, Nabeshima Y, Nakamura K, Kuro-o M, Kawaguchi H. Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Mineral Res 2002; 17: 1744-1751
    CrossrefPubMedSearch in Google Scholar
  • 16 Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 2004; 29: 91-99
    CrossrefPubMedSearch in Google Scholar
  • 17 Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004; 565: 143-147
    CrossrefPubMedSearch in Google Scholar
  • 18 Wang X, Sun Z. RNAi silencing of brain klotho potentiates cold-induced elevation of blood pressure via the endothelin pathway. Physiol Genom 2010; 41: 120-126
    CrossrefPubMedSearch in Google Scholar
  • 19 Belin de Chantemele EJ, Mintz JD, Rainey WE, Stepp DW. Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice. Hypertension 2011; 58: 271-279
    CrossrefPubMedSearch in Google Scholar
  • 20 Amagasa S, Takahashi T, Takaoka S, Horikawa H. Effects of halothane and isoflurane anesthesia on sympathetic adrenal nerve responses to carbon dioxide challenge in rats. J Anesth 1993; 7: 454-461
    CrossrefPubMedSearch in Google Scholar
  • 21 Hoffman WE, Edelman G, Ripper R, Koenig HM. Sodium nitroprusside compared with isoflurane-induced hypotension: the effects on brain oxygenation and arteriovenous shunting. Anesth Analg 2001; 93: 166-170
    PubMedSearch in Google Scholar
  • 22 Kang BT, Leoni RF, Kim DE, Silva AC. Phenylephrine-induced hypertension during transient middle cerebral artery occlusion alleviates ischemic brain injury in spontaneously hypertensive rats. Brain Res 2012; 1477: 83-91
    CrossrefPubMedSearch in Google Scholar
  • 23 Kim EK, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 2004; 279: 19970-19976
    CrossrefPubMedSearch in Google Scholar
  • 24 Mohammadi Z, Dorkoosh FA, Hosseinkhani S, Gilani K, Amini T, Najafabadi AR, Tehrani MR. In vivo transfection study of chitosan-DNA-FAP-B nanoparticles as a new non viral vector for gene delivery to the lung. International journal of pharmaceutics 2011; 421: 183-188
    CrossrefPubMedSearch in Google Scholar
  • 25 Oliveira DR, Santos RA, Santos GF, Khosla M, Campagnole-Santos MJ. Changes in the baroreflex control of heart rate produced by central infusion of selective angiotensin antagonists in hypertensive rats. Hypertension 1996; 27: 1284-1290
    CrossrefPubMedSearch in Google Scholar
  • 26 Valenti VE, Ferreira C, Meneghini A, Ferreira M, Murad N, Ferreira Filho C, Correa JA, Abreu LC, Colombari E. Evaluation of baroreflex function in young spontaneously hypertensive rats. Arquiv Brasil Cardiol 2009; 92: 205-215
    PubMedSearch in Google Scholar
  • 27 Valenti VE, Imaizumi C, de Abreu LC, Colombari E, Sato MA, Ferreira C. Intra-strain variations of baroreflex sensitivity in young Wistar-Kyoto rats. Clin Investig Med 2009; 32: E251
    PubMedSearch in Google Scholar
  • 28 Kato Y, Arakawa E, Kinoshita S, Shirai A, Furuya A, Yamano K, Nakamura K, Iida A, Anazawa H, Koh N, Iwano A, Imura A, Fujimori T, Kuro-o M, Hanai N, Takeshige K, Nabeshima Y. Establishment of the anti-Klotho monoclonal antibodies and detection of Klotho protein in kidneys. Biochem Biophys Res Commun 2000; 267: 597-602
    CrossrefPubMedSearch in Google Scholar
  • 29 Takumida M, Ishibashi T, Hamamoto T, Hirakawa K, Anniko M. Age-dependent changes in the expression of klotho protein, TRPV5 and TRPV6 in mouse inner ear. Acta Oto-Laryngol 2009; 129: 1340-1350
    CrossrefPubMedSearch in Google Scholar
  • 30 Kamemori M, Ohyama Y, Kurabayashi M, Takahashi K, Nagai R, Furuya N. Expression of Klotho protein in the inner ear. Hearing Res 2002; 171: 103-110
    CrossrefPubMedSearch in Google Scholar
  • 31 Wang Y, Sun Z. Current understanding of klotho. Age Res Rev 2009; 8: 43-51
    CrossrefPubMedSearch in Google Scholar
  • 32 Takeshita K, Fujimori T, Kurotaki Y, Honjo H, Tsujikawa H, Yasui K, Lee JK, Kamiya K, Kitaichi K, Yamamoto K, Ito M, Kondo T, Iino S, Inden Y, Hirai M, Murohara T, Kodama I, Nabeshima Y. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation 2004; 109: 1776-1782
    CrossrefPubMedSearch in Google Scholar
  • 33 Saito Y, Yamagishi T, Nakamura T, Ohyama Y, Aizawa H, Suga T, Matsumura Y, Masuda H, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R. Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun 1998; 248: 324-329
    CrossrefPubMedSearch in Google Scholar
  • 34 Saigusa T, Iriki M, Arita J. Brain angiotensin II tonically modulates sympathetic baroreflex in rabbit ventrolateral medulla. Am J Physiol 1996; 271: H1015-H1021
    PubMedSearch in Google Scholar
  • 35 Gutterman DD, Arthur JM, Pardubsky PD, Gebhart GF, Marcus ML, Brody MJ. Role of medullary lateral reticular formation in baroreflex coronary vasoconstriction. Brain research 1991; 557: 202-209
    CrossrefPubMedSearch in Google Scholar
  • 36 Hildreth CM, Goodchild AK. Role of ionotropic GABA, glutamate and glycine receptors in the tonic and reflex control of cardiac vagal outflow in the rat. BMC Neurosci 2010; 11: 128
    CrossrefPubMedSearch in Google Scholar
  • 37 Andresen MC, Yang M. Arterial baroreceptor resetting: contributions of chronic and acute processes. Clin Exp Pharmacol Physiol 1989; 15 (Suppl) 19-30
    PubMedSearch in Google Scholar
  • 38 Ishizuka Y, Miura Y, Kimura S, Ohashi H, Sugawara T, Watanabe H, Noshiro T, Takahashi M, Sano N, Yoshinaga K. The baroreflex-mediated changes in plasma norepinephrine and heart rate in patients with essential hypertension. Jap Circul J 1987; 51: 1165-1173
    CrossrefPubMedSearch in Google Scholar
  • 39 Matsukawa T, Gotoh E, Hasegawa O, Shionoiri H, Tochikubo O, Ishii M. Reduced baroreflex changes in muscle sympathetic nerve activity during blood pressure elevation in essential hypertension. J Hypertension 1991; 9: 537-542
    CrossrefPubMedSearch in Google Scholar
  • 40 Monteiro MM, Franca-Silva MS, Alves NF, Porpino SK, Braga VA. Quercetin improves baroreflex sensitivity in spontaneously hypertensive rats. Molecules 2012; 17: 12997-13008
    CrossrefPubMedSearch in Google Scholar
  • 41 Sanches IC, de Oliveira Brito J, Candido GO, da Silva Dias D, Jorge L, Irigoyen MC, De Angelis K. Cardiometabolic benefits of exercise training in an experimental model of metabolic syndrome and menopause. Menopause 2012; 19: 562-568
    CrossrefPubMedSearch in Google Scholar
  • 42 Tsyrlin VA, Galagudza MM, Kuzmenko NV, Pliss MG, Rubanova NS, Shcherbin YI. Arterial baroreceptor reflex counteracts long-term blood pressure increase in the rat model of renovascular hypertension. PloS One 2013; 8: e64788
    CrossrefPubMedSearch in Google Scholar
  • 43 Stern JE, Sonner PM, Son SJ, Silva FC, Jackson K, Michelini LC. Exercise training normalizes an increased neuronal excitability of NTS-projecting neurons of the hypothalamic paraventricular nucleus in hypertensive rats. J Neurophysiol 2012; 107: 2912-2921
    CrossrefPubMedSearch in Google Scholar
  • 44 Kawada T, Shimizu S, Kamiya A, Sata Y, Uemura K, Sugimachi M. Dynamic characteristics of baroreflex neural and peripheral arcs are preserved in spontaneously hypertensive rats. Am J Physiol Regul Integ Comp Physiol 2011; 300: R155-R165
    CrossrefPubMedSearch in Google Scholar
  • 45 Nijsen MJ, de Ruiter GJ, Kasbergen CM, de Wildt DJ. Effect of gamma-melanocyte-stimulating hormones on baroreflex sensitivity and cerebral blood flow autoregulation in rats. Cardiovasc Res 2001; 49: 226-233
    CrossrefPubMedSearch in Google Scholar
  • 46 Hatton R, Clough D, Faulkner K, Conway J. Angiotensin-converting enzyme inhibitor resets baroreceptor reflexes in conscious dogs. Hypertension 1981; 3: 676-681
    CrossrefPubMedSearch in Google Scholar
  • 47 Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt KP, Kuro-o M. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 2005; 280: 38029-38034
    CrossrefPubMedSearch in Google Scholar
  • 48 Lu P, Boros S, Chang Q, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho exclusively activates the epithelial Ca2+ channels TRPV5 and TRPV6. Nephrol Dial Transplant 2008; 23: 3397-3402
    CrossrefPubMedSearch in Google Scholar
  • 49 Mensenkamp AR, Hoenderop JG, Bindels RJ. TRPV5, the gateway to Ca2+ homeostasis. Handbook Exp Pharmacol 2007; 207-220
    PubMedSearch in Google Scholar