title: Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure.
abstract: FSGS is the most common primary glomerular disease underlying ESRD in the United States and is increasing in incidence globally. FSGS results from podocyte injury, yet the mechanistic details of disease pathogenesis remain unclear. This has resulted in an unmet clinical need for cell-specific therapy in the treatment of FSGS and other proteinuric kidney diseases. We previously identified Yes-associated protein (YAP) as a prosurvival signaling molecule, the in vitro silencing of which increases podocyte susceptibility to apoptotic stimulus. YAP is a potent oncogene that is a prominent target for chemotherapeutic drug development. In this study, we tested the hypothesis that podocyte-specific deletion of Yap leads to proteinuric kidney disease through increased podocyte apoptosis. Yap was selectively silenced in podocytes using Cre-mediated recombination controlled by the podocin promoter. Yap silencing in podocytes resulted in podocyte apoptosis, podocyte depletion, proteinuria, and an increase in serum creatinine. Histologically, features characteristic of FSGS, including mesangial sclerosis, podocyte foot process effacement, tubular atrophy, interstitial fibrosis, and casts, were observed. In human primary FSGS, we noted reduced glomerular expression of YAP. Taken together, these results suggest a role for YAP as a physiologic antagonist of podocyte apoptosis, the signaling of which is essential for maintaining the integrity of the glomerular filtration barrier. These data suggest potential nephrotoxicity with strategies directed toward inhibition of YAP function. Further studies should evaluate the role of YAP in proteinuric glomerular disease pathogenesis and its potential utility as a therapeutic target.
authors.affiliation: Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Monica
authors.initials: M
authors.lastname: Schwartzman
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
authors.forename: Antoine
authors.initials: A
authors.lastname: Reginensi
authors.affiliation: Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Jenny S
authors.initials: JS
authors.lastname: Wong
authors.affiliation: Department of Research, Morphometry and Stereology Laboratory, Charles R. Drew University of Medicine and Science, Los Angeles, California;
authors.forename: John M
authors.initials: JM
authors.lastname: Basgen
authors.affiliation: Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Kristin
authors.initials: K
authors.lastname: Meliambro
authors.affiliation: Department of Research, Morphometry and Stereology Laboratory, Charles R. Drew University of Medicine and Science, Los Angeles, California; Department of Medicine, Division of Nephrology, University of California Los Angeles, Los Angeles, California; and.
authors.forename: Susanne B
authors.initials: SB
authors.lastname: Nicholas
authors.affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada;
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
authors.affiliation: Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; kirk.campbell@mssm.edu.
authors.forename: Kirk N
authors.initials: KN
authors.lastname: Campbell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D018797:Cell Cycle Proteins; D018450:Disease Progression; D017353:Gene Deletion; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics*; D050199:Podocytes / Q000502:physiology*; D051437:Renal Insufficiency / Q000235:genetics*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse
keywords: focal segmental glomerulosclerosis; glomerular disease; podocyte