title: Differential Regulatory Role of Soluble Klothos on Cardiac Fibrogenesis in Hypertension.
abstract: Soluble Klotho functions as an endocrine factor that plays important roles in a variety of pathophysiological processes. Soluble Klotho contains 130 KDa and 65 KDa isoforms. However, their distinct individual functional heterogeneity remains uncertain. Herein, we investigated the regulatory role of two soluble Klothos on cardiac fibrogenic responses.
  
  
  
  The effect of soluble Klothos on myofibroblast differentiation, proliferation, and collagen synthesis/degradation were examined in cultured mouse cardiac myofibroblasts. The role of 130 KDa Klotho on fibrosis in hypertensive heart disease were examined in wild type (WT) and Klotho transgenic (Tg/+) mice receiving chronic angiotensin (Ang)II infusion. Our in vitro studies revealed that addition of 130 KDa soluble Klotho isoform increased collagen synthesis in a dose dependent manner. Furthermore, 130 KDa Klotho significantly stimulated myofibroblast differentiation, proliferation, and ERK phosphorylation, which were abolished by fibroblast growth factor (FGF) receptor antagonist (SU5402). In contrast, 65 KDa soluble Klotho treatment significantly suppressed myofibroblast proliferation and collagen synthesis. In vivo study further demonstrated that chronic AngII infusion lead to cardiac fibrosis in both WT and Tg/+ mice. However, cardiac collagen, TGF-β1, TIMP-2, and α-smooth muscle actin (SMA) levels were markedly upregulated in Tg/+ mice compared to WT cohort.
  
  
  
  Taken together, these findings implicate that 130 KDa soluble Klotho plays a stimulatory role in cardiac myofibroblast growth and activity through FGF pathway, whereas 65 KDa soluble Klotho exerts an anti-fibrotic effect in cardiac myofibroblasts. Thus, two distinct isoforms of soluble Klotho appear to play the counter-regulatory roles in cardiac fibrogenic responses.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, China;
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Cody W
authors.initials: CW
authors.lastname: McCoy
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Darryl L
authors.initials: DL
authors.lastname: Quarles
authors.affiliation: Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Min
authors.initials: M
authors.lastname: Pi
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Gwendalyn
authors.initials: G
authors.lastname: King
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN; yasun@uthsc.edu.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology*; D002454:Cell Differentiation; D024042:Collagen Type I / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005355:Fibrosis; D005966:Glucuronidase / Q000502:physiology*; D006973:Hypertension / Q000150:complications*; D000090265:Klotho Proteins; D008297:Male; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000502:physiology*; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D020033:Protein Isoforms; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: blood pressure; cardiac fibrosis; hypertension; hypertensive heart disease; myofibroblasts; soluble klotho.