FGF23 induces left ventricular hypertrophy

被引：1672

作者：

Faul, Christian ^{[1
,2
]}

Amaral, Ansel P. ^{[1
,2
]}

Oskouei, Behzad ^{[3
]}

Hu, Ming-Chang ^{[4
,5
,6
]}

Sloan, Alexis ^{[1
,2
]}

Isakova, Tamara ^{[1
]}

Gutierrez, Orlando M. ^{[7
,8
]}

Aguillon-Prada, Robier ^{[1
]}

Lincoln, Joy ^{[9
,10
]}

Hare, Joshua M. ^{[3
]}

Mundel, Peter ^{[11
]}

Morales, Azorides ^{[12
]}

Scialla, Julia ^{[1
]}

Fischer, Michael ^{[13
,14
,15
]}

Soliman, Elsayed Z. ^{[16
]}

Chen, Jing ^{[17
]}

Go, Alan S. ^{[18
,19
,20
,21
]}

Rosas, Sylvia E. ^{[22
]}

Nessel, Lisa ^{[23
]}

Townsend, Raymond R. ^{[22
]}

Feldman, Harold I. ^{[22
,23
]}

Sutton, Martin St. John ^{[24
]}

Ojo, Akinlolu ^{[26
]}

Gadegbeku, Crystal ^{[25
]}

Di Marco, Giovana Seno ^{[27
]}

Reuter, Stefan ^{[27
]}

Kentrup, Dominik ^{[27
]}

Tiemann, Klaus ^{[28
]}

Brand, Marcus ^{[27
]}

Hill, Joseph A. ^{[4
,29
]}

Moe, Orson W. ^{[4
,30
]}

Kuro-o, Makoto ^{[6
,31
]}

Kusek, John W. ^{[32
]}

Keane, Martin G. ^{[24
]}

Wolf, Myles ^{[1
]}

机构：

[1] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA

[2] Univ Miami, Miller Sch Med, Dept Cell Biol & Anat, Miami, FL 33136 USA

[3] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA

[6] Univ Texas SW Med Ctr Dallas, Charles & Jane Pak Ctr Mineral Metab & Clin Res, Dallas, TX 75390 USA

[7] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA

[8] Univ Alabama Birmingham, Sch Med, Dept Med, Div Nephrol, Birmingham, AL USA

[9] Univ Miami, Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL 33136 USA

[10] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA

[11] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Renal Unit, Boston, MA USA

[12] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA

[13] Jesse Brown VA Med Ctr, Dept Med, Chicago, IL USA

[14] Univ Illinois, Med Ctr, Chicago, IL USA

[15] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA

[16] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr, Winston Salem, NC USA

[17] Tulane Sch Med, Dept Med, New Orleans, LA USA

[18] Kaiser Permanente No Calif, Div Res, San Francisco, CA USA

[19] UCSF, Dept Epidemiol, San Francisco, CA USA

[20] UCSF, Dept Biostat, San Francisco, CA USA

[21] UCSF, Dept Med, San Francisco, CA USA

[22] Univ Penn, Sch Med, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA

[23] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA

[24] Univ Penn, Sch Med, Dept Med, Div Cardiol, Philadelphia, PA 19104 USA

[25] Temple Univ, Schostl Med, Dept Internal Med, Sect Nephrol & Kidney Transplantat, Philadelphia, PA 19122 USA

[26] Univ Michigan Hlth Syst, Dept Internal Med, Ann Arbor, MI USA

[27] Univ Munster, Dept Internal Med D, D-4400 Munster, Germany

[28] Univ Munster, Dept Cardiol & Angiol, Munster, Germany

[29] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA

[30] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA

[31] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[32] NIDDK, Bethesda, MD USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2011年 / 121卷 / 11期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR; 23; MYOSIN HEAVY-CHAIN; STAGE RENAL-DISEASE; CHRONIC KIDNEY-DISEASE; CARDIAC-HYPERTROPHY; MYOCARDIAL PERFORMANCE; CRYSTAL-STRUCTURE; GENE-EXPRESSION; PROTEIN; HEART;

D O I：

10.1172/JCI46122

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intrarnyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

引用

页码：4393 / 4408

页数：16

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