A Review of the Effects of the FGF23-Klotho Endocrine Axis on Blood Vessels of Brain and Stroke

doi:10.3969/j.issn.1673-5765.2024.04.010

Abstract

Abstract: Fibroblast growth factor 23 (FGF23) -Klotho endocrine axis is involved in phosphate metabolism, and is closely related to the pathogenesis of stroke. FGF23 and Klotho levels are associated with the incidence and prognosis of stroke. The FGF23-Klotho endocrine axis is involved in the regulation of vascular inflammation and may be involved in the pathological process of stroke risk factors such as hypertension, insulin resistance, lipid metabolism and obesity. In this paper, the influence and mechanism of FGF23-Klotho endocrine axis on stroke were reviewed in order to bring new ideas for clinical treatment and prevention of stroke.

Key words: Stroke; Fibroblast growth factor 23; Klotho protein

摘要： 成纤维细胞生长因子23（fibroblast growth factor 23，FGF23）-Klotho内分泌轴参与磷酸盐代谢，研究提示该内分泌轴与卒中的发病机制密切相关。FGF23、Klotho水平均与卒中的发病及预后有关。FGF23-Klotho内分泌轴参与调节血管壁炎症反应，并可能参与高血压、胰岛素抵抗、脂代谢及肥胖等卒中危险因素的病理过程。本文介绍FGF23-Klotho内分泌轴对卒中的影响及可能机制的相关研究进展，以期为临床治疗和预防卒中带来新的思路。

关键词: 卒中; 成纤维细胞生长因子23; Klotho蛋白

CLC Number:

SONG Xiao, LU Keliang, WU Chunyan. A Review of the Effects of the FGF23-Klotho Endocrine Axis on Blood Vessels of Brain and Stroke[J]. Chinese Journal of Stroke, 2024, 19(4): 468-473.

宋晓, 卢克良, 吴春艳. FGF23-Klotho内分泌轴对脑血管及卒中的影响综述[J]. 中国卒中杂志, 2024, 19(4): 468-473.

References

[1] KURO-O M. The Klotho proteins in health and disease[J]. Nat Rev Nephrol，2019，15（1）：27-44.
[2] KUROSU H，OGAWA Y，MIYOSHI M，et al. Regulation of fibroblast growth factor-23 signaling by Klotho[J]. J Biol Chem，2006，281（10）：6120-6123.
[3] KURO-O M. Phosphate and Klotho[J/OL]. Kidney Int，2011，79121：S20-3[2023-09-09]. https://doi.org/10.1038/ki.2011.26.
[4] LANZANI C，CITTERIO L，VEZZOLI G. Klotho：a link between cardiovascular and non-cardiovascular mortality[J]. Clin Kidney J，2020，13（6）：926-932.
[5] KANBAY M，VERVLOET M，COZZOLINO M，et al. Novel faces of fibroblast growth factor 23（FGF23）：iron deficiency，inflammation，insulin resistance，left ventricular hypertrophy，proteinuria and acute kidney injury[J]. Calcif Tissue Int，2017，100（3）：217-228.
[6] ITOH N，ORNITZ D M. Fibroblast growth factors：from molecular evolution to roles in development，metabolism and disease[J]. J Biochem，2011，149（2）：121-130.
[7] HU M C，SHIIZAKI K，KURO-O M，et al. Fibroblast growth factor 23 and Klotho：physiology and pathophysiology of an endocrine network of mineral metabolism[J/OL]. Annu Rev Physiol，2013，75：503-533[2023-09-10]. https://doi.org/10.1146/annurev-physiol-030212-183727.
[8] MOHAMMADI M，OLSEN S K，IBRAHIMI O A. Structural basis for fibroblast growth factor receptor activation[J]. Cytokine Growth Factor Rev，2005，16（2）：107-137.
[9] GOETZ R，BEENKEN A，IBRAHIMI O A，et al. Molecular insights into the Klotho-dependent，endocrine mode of action of fibroblast growth factor 19 subfamily members[J]. Mol Cell Biol，2007，27（9）：3417-3428.
[10] LIM K，GROEN A，MOLOSTVOV G，et al. α-Klotho expression in human tissues[J/OL]. J Clin Endocrinol Metab，2015，100（10）：E1308-18[2023-09-10]. https://doi.org/10.1210/jc.2015-1800.
[11] FUNG T Y，IYASWAMY A，SREENIVASMURTHY S G，et al. Klotho an autophagy stimulator as a potential therapeutic target for Alzheimer’s disease：a review[J/OL]. Biomedicines，2022，10（3）：705[2023-09-10]. https://doi.org/10.3390/biomedicines10030705.
[12] LASZCZYK A M，NETTLES D，POLLOCK T A，et al. FGF-23 deficiency impairs hippocampal-dependent cognitive function[J/OL]. eNeuro，2019，6（2）：ENEURO.0469-18.2019[2023-09-10]. https://doi.org/10.1523/ENEURO.0469-18.2019.
[13] KUNERT S K，HARTMANN H，HAFFNER D，et al. Klotho and fibroblast growth factor 23 in cerebrospinal fluid in children[J]. J Bone Miner Metab，2017，35（2）：215-226.
[14] SVENSSON E H，SÖDERHOLM M. Fibroblast growth factor 23 is associated with risk of intracerebral hemorrhage[J]. Eur J Neurol，2022，29（1）：114-120.
[15] LIU M L，XIA P P，TAN Z Q，et al. Fibroblast growth factor-23 and the risk of cardiovascular diseases and mortality in the general population：a systematic review and dose-response meta-analysis[J/OL]. Front Cardiovasc Med，2022，9：989574
[2023-09-10]. https://doi.org/10.3389/fcvm.2022.989574.
[16] BROMBO G，BONETTI F，ORTOLANI B，et al. Lower plasma Klotho concentrations are associated with vascular dementia but not late-onset Alzheimer’s disease[J]. Gerontology，2018，64（5）：414-421.
[17] LEE J B，WOO H G，CHANG Y，et al. Plasma Klotho concentrations predict functional outcome at three months after acute ischemic stroke patients[J]. Ann Med，2019，51（3/4）：262-269.
[18] YOKOYAMA S，OGURO R，YAMAMOTO K，et al. A Klotho gene single nucleotide polymorphism is associated with the onset of stroke and plasma Klotho concentration[J]. Aging（Albany NY），2018，11（1）：104-114.
[19] DU H P，GUO T T，YE H，et al. The association between serum phosphorus and common carotid artery intima-media thickness in ischemic stroke patients[J/OL]. Front Neurol，2023，14：1172488[2023-09-10]. https://doi.org/10.3389/fneur.2023.1172488.
[20] LV W J，CUI C，WANG Z X，et al. A high serum phosphate and calcium-phosphate product is associated with cerebral small vascular disease in patients with stroke：a real-world study[J/OL]. Front Nutr，2022，9：801667[2023-09-10]. https://doi.org/10.3389/fnut.2022.801667.
[21] YAMADA S，TOKUMOTO M，TATSUMOTO N，et al. Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia[J/OL]. Am J Physiol Renal Physiol，2014，306（12）：F1418-28[2023-09-10]. https://doi.org/10.1152/ajprenal.00633.2013.
[22] COZZOLINO M，CICERI P，GALASSI A，et al. The key role of phosphate on vascular calcification[J/OL]. Toxins（Basel），2019，11（4）：213[2023-09-10]. https://doi.org/10.3390/toxins11040213.
[23] ASENJO-BUENO A，ALCALDE-ESTÉVEZ E，EL ASSAR M，et al. Hyperphosphatemia-induced oxidant/antioxidant imbalance impairs vascular relaxation and induces inflammation and fibrosis in old mice[J/OL]. Antioxidants（Basel），2021，10（8）：1308[2023-09-10]. https://doi.org/10.3390/antiox10081308.
[24] VILLA-BELLOSTA R，SORRIBAS V. Phosphonoformic acid prevents vascular smooth muscle cell calcification by inhibiting calcium-phosphate deposition[J]. Arterioscler Thromb Vasc Biol，2009，29（5）：761-766.
[25] CAI M M，SMITH E R，BRUMBY C，et al. Fetuin-A-containing calciprotein particle levels can be reduced by dialysis，sodium thiosulphate and plasma exchange. Potential therapeutic implications for calciphylaxis？[J]. Nephrology（Carlton），2013，18（11）：724-727.
[26] MARSELL R，KRAJISNIK T，GÖRANSSON H，et al. Gene expression analysis of kidneys from transgenic mice expressing fibroblast growth factor-23[J]. Nephrol Dial Transplant，2008，23（3）：827-833.
[27] ZHU L，STEIN L R，KIM D，et al. Klotho controls the brain-immune system interface in the choroid plexus[J/OL]. Proc Natl Acad Sci U S A，2018，115（48）：E11388-E11396[2023-09-09]. https://doi.org/10.1073/pnas.1808609115.
[28] 中华医学会神经病学分会，中华医学会神经病学分会脑血管病学组. 中国缺血性卒中和短暂性脑缺血发作二级预防指南2022[J]. 中华神经科杂志，2022，55（10）：1071-1110.
Chinese Society of Neurology，Chinese Stroke Society. Chinese guideline for the secondary prevention of ischemic stroke and transient ischemic attack 2022[J]. Chin J Neurol，2022，55（10）：1071-1110.
[29] PI M，YE R S，HAN X B，et al. Cardiovascular interactions between fibroblast growth factor-23 and angiotensin Ⅱ[J/OL]. Sci Rep，2018，8（1）：12398[2023-09-09]. https://doi.org/10.1038/s41598-018-30098-1.
[30] DAI B，DAVID V，MARTIN A，et al. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model[J/OL]. PLoS One，2012，7（9）：e44161[2023-09-09]. https://doi.org/10.1371/journal.pone.0044161.
[31] DE BORST M H，VERVLOET M G，TER WEE P M，et al. Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-Klotho in chronic kidney disease[J]. J Am Soc Nephrol，2011，22（9）：1603-1609.
[32] ZHOU L L，MO H Y，MIAO J H，et al. Klotho ameliorates kidney injury and fibrosis and normalizes blood pressure by targeting the renin-angiotensin system[J]. Am J Pathol，2015，185（12）：3211-3223.
[33] PATHARE G，ANDEREGG M，ALBANO G，et al. Elevated FGF23 levels in mice lacking the thiazide-sensitive NaCl cotransporter（NCC）[J/OL]. Sci Rep，2018，8（1）：3590[2023-09-10]. https://doi.org/10.1038/s41598-018-22041-1.
[34] CITTERIO L，DELLI CARPINI S，LUPOLI S，et al. Klotho gene in human salt-sensitive hypertension[J]. Clin J Am Soc Nephrol，2020，15（3）：375-383.
[35] HU M C，KURO-O M，MOE O W. The emerging role of Klotho in clinical nephrology[J]. Nephrol Dial Transplant，2012，27（7）：2650-2657.
[36] LIU T L，WEN H Y，LI H，et al. Oleic acid attenuates ang Ⅱ（angiotensin Ⅱ）-induced cardiac remodeling by inhibiting FGF23（fibroblast growth factor 23）expression in mice[J]. Hypertension，2020，75（3）：680-692.
[37] MAHMOUD D M，ALI M R A，ALDOSARI B N，et al. Functional candesartan loaded lipid nanoparticles for the control of diabetes-associated stroke：in vitro and in vivo studies[J/OL]. Int J Pharm X，2024，7：100227[2023-09-10]. https://doi.org/10.1016/j.ijpx.2023.100227.
[38] KEUPER M，HÄRING H U，STAIGER H. Circulating FGF21 levels in human health and metabolic disease[J]. Exp Clin Endocrinol Diabetes，2020，128（11）：752-770.
[39] LIN Y，SUN Z J. In vivo pancreatic β-cell-specific expression of antiaging gene Klotho：a novel approach for preserving β-cells in type 2 diabetes[J]. Diabetes，2015，64（4）：1444-1458.
[40] TYPIAK M，PIWKOWSKA A. Antiinflammatory actions of Klotho：implications for therapy of diabetic nephropathy[J/OL]. Int J Mol Sci，2021，22（2）：956[2023-09-10]. https://doi.org/10.3390/ijms22020956.
[41] RAO Z J，LANDRY T，LI P X，et al. Administration of alpha Klotho reduces liver and adipose lipid accumulation in obese mice[J/OL]. Heliyon，2019，5（4）：e01494[2023-09-10]. https://doi.org/10.1016/j.heliyon.2019.e01494.
[42] STROM T M，JÜPPNER H. PHEX，FGF23，DMP1 and beyond[J]. Curr Opin Nephrol Hypertens，2008，17（4）：357-362.
[43] NOONAN M L，WHITE K E. FGF23 synthesis and activity[J]. Curr Mol Biol Rep，2019，5（1）：18-25.
[44] JIA G H，AROOR A R，JIA C，et al. Endothelial cell senescence in aging-related vascular dysfunction[J]. Biochim Biophys Acta Mol Basis Dis，2019，1865（7）：1802-1809.
[45] CAI Y Y，ZHANG H B，FAN C X，et al. Renoprotective effects of brown adipose tissue activation in diabetic mice[J]. J Diabetes，2019，11（12）：958-970.