title: Cardiac myocyte-derived follistatin-like 1 prevents renal injury in a subtotal nephrectomy model.
abstract: Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectomy. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectomy led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-α-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glomerular and tubulointerstitial damage in the kidney.
authors: Departments of *Cardiology and.
authors: Satoko
authors: S
authors: Hayakawa
authors: Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; nouchi@med.nagoya-u.ac.jp ohashik@med.nagoya-u.ac.jp.
authors: Koji
authors: K
authors: Ohashi
authors: Departments of *Cardiology and.
authors: Rei
authors: R
authors: Shibata
authors: Departments of *Cardiology and.
authors: Yoshiyuki
authors: Y
authors: Kataoka
authors: Departments of *Cardiology and.
authors: Megumi
authors: M
authors: Miyabe
authors: Departments of *Cardiology and.
authors: Takashi
authors: T
authors: Enomoto
authors: Departments of *Cardiology and.
authors: Yusuke
authors: Y
authors: Joki
authors: Departments of *Cardiology and.
authors: Yuuki
authors: Y
authors: Shimizu
authors: Departments of *Cardiology and.
authors: Takahiro
authors: T
authors: Kambara
authors: Departments of *Cardiology and.
authors: Yusuke
authors: Y
authors: Uemura
authors: Departments of *Cardiology and.
authors: Daisuke
authors: D
authors: Yuasa
authors: Departments of *Cardiology and.
authors: Hayato
authors: H
authors: Ogawa
authors: Departments of *Cardiology and.
authors: Kazuhiro
authors: K
authors: Matsuo
authors: Departments of *Cardiology and.
authors: Mizuho
authors: M
authors: Hiramatsu-Ito
authors: Department of Anatomy, Embryology & Physiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands; and.
authors: Maurice J B
authors: MJ
authors: van den Hoff
authors: Molecular Cardiology, Boston University School of Medicine, Boston, Massachusetts.
authors: Kenneth
authors: K
authors: Walsh
authors: Departments of *Cardiology and.
authors: Toyoaki
authors: T
authors: Murohara
authors: Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; nouchi@med.nagoya-u.ac.jp ohashik@med.nagoya-u.ac.jp.
authors: Noriyuki
authors: N
authors: Ouchi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D038702:Follistatin-Related Proteins / Q000502:physiology*; D050527:Mesangial Cells / Q000502:physiology; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D009392:Nephrectomy; D051436:Renal Insufficiency, Chronic / Q000209:etiology*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D055372:AMP-Activated Protein Kinases
keywords: albuminuria; cardiovascular; cell signaling; chronic inflammation; mesangial cells; renal injury