title: Four-and-a-Half LIM Domains Protein 2 Is a Coactivator of Wnt Signaling in Diabetic Kidney Disease.
abstract: Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/β-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-β1, activated FHL2 protein and Wnt/β-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/β-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2(+/+) mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2(+/+) mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactions with β-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/β-catenin-induced podocytopathy.
authors: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan;
authors: Szu-Yuan
authors: SY
authors: Li
authors: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan;
authors: Po-Hsun
authors: PH
authors: Huang
authors: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan;
authors: Der-Cherng
authors: DC
authors: Tarng
authors: Department of Urology, Taipei Veterans General Hospital, Department of Urology, School of Medicine, National Yang-Ming University, Taipei, Taiwan;
authors: Tzu-Ping
authors: TP
authors: Lin
authors: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan;
authors: Wu-Chang
authors: WC
authors: Yang
authors: Department of Urology, Taipei Veterans General Hospital, Department of Urology, School of Medicine, National Yang-Ming University, Taipei, Taiwan;
authors: Yen-Hwa
authors: YH
authors: Chang
authors: Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, and Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan;
authors: An-Hang
authors: AH
authors: Yang
authors: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan;
authors: Chih-Ching
authors: CC
authors: Lin
authors: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan;
authors: Muh-Hwa
authors: MH
authors: Yang
authors: Department of Medical Research, Taipei Veterans General Hospital, Institute and Department of Pharmacology, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan;
authors: Jaw-Wen
authors: JW
authors: Chen
authors: The Institute of Engineering in Medicine, University of California San Diego, La Jolla, California;
authors: Geert W
authors: GW
authors: Schmid-Schönbein
authors: Departments of Bioengineering, Nanoengineering, Institute of Engineering in Medicine, University of California San Diego, La Jolla, California; and.
authors: Shu
authors: S
authors: Chien
authors: Division of Cardiology, Department of Internal Medicine; Healthcare Center; Heart Failure Center, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan pchu@adm.cgmh.org.tw huangbs@vghtpe.gov.tw.
authors: Pao-Hsien
authors: PH
authors: Chu
authors: Department of Medical Research, Taipei Veterans General Hospital, Institute and Department of Pharmacology, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan;
authors: Shing-Jong
authors: SJ
authors: Lin
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D055786:Gene Knockout Techniques; D050533:Glomerular Basement Membrane / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C105987:FHL2 protein, human; C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D005947:Glucose
keywords: diabetes; podocyte; proteinuria