title: Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling.
abstract: Mechanisms of epithelial cell renewal remain poorly understood in the mammalian kidney, particularly in the glomerulus, a site of cellular damage in chronic kidney disease. Within the glomerulus, podocytes--differentiated epithelial cells crucial for filtration--are thought to lack substantial capacity for regeneration. Here we show that podocytes rapidly lose differentiation markers and enter the cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression in mice induces marked upregulation of Wnt signaling and disrupts glomerular structure, resulting in a collapsing glomerulopathy resembling those in human disease, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased expression of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Silencing transgenic TERT expression or inhibiting Wnt signaling through systemic expression of the Wnt inhibitor Dkk1 in either TERT transgenic mice or in a mouse model of HIVAN results in marked normalization of podocytes, including rapid cell-cycle exit, re-expression of differentiation markers and improved filtration barrier function. These data reveal an unexpected capacity of podocytes to reversibly enter the cell cycle, suggest that podocyte renewal may contribute to glomerular homeostasis and implicate the telomerase and Wnt-β-catenin pathways in podocyte proliferation and disease.
authors.affiliation: Department of Medicine, Stanford School of Medicine, Stanford, California, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Shkreli
authors.forename: Kavita Y
authors.initials: KY
authors.lastname: Sarin
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Pech
authors.forename: Natalia
authors.initials: N
authors.lastname: Papeta
authors.forename: Woody
authors.initials: W
authors.lastname: Chang
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Brockman
authors.forename: Peggie
authors.initials: P
authors.lastname: Cheung
authors.forename: Eunice
authors.initials: E
authors.lastname: Lee
authors.forename: Frank
authors.initials: F
authors.lastname: Kuhnert
authors.forename: Jean L
authors.initials: JL
authors.lastname: Olson
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: Steven E
authors.initials: SE
authors.lastname: Artandi
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D019098:Telomerase; C509187:Tert protein, mouse