Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling

• Published in: Nature medicine Vol. 18; no. 1; pp. 111 - 119
• Main Authors: Shkreli, Marina, Sarin, Kavita Y, Pech, Matthew F, Papeta, Natalia, Chang, Woody, Brockman, Stephanie A, Cheung, Peggie, Lee, Eunice, Kuhnert, Frank, Olson, Jean L, Kuo, Calvin J, Gharavi, Ali G, D'Agati, Vivette D, Artandi, Steven E
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2012; Nature Publishing Group
• Subjects: 631/443/272/1684/1587/2101; 631/532/2441; 631/61/490; 692/699/1585/2759; AIDS-Associated Nephropathy - genetics; AIDS-Associated Nephropathy - metabolism; Animals; Apoptosis; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell cycle; Cell Differentiation; Cell Proliferation; Cellular signal transduction; Disease Models, Animal; Epithelial cells; Gene Expression Regulation; Human immunodeficiency virus; Humans; Infectious Diseases; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Kidney - cytology; Kidney - metabolism; Kidney Glomerulus - cytology; Kidney Glomerulus - growth & development; Kidney Glomerulus - metabolism; Kidneys; Mammals; Metabolic Diseases; Mice; Mice, Transgenic; Molecular Medicine; Neurosciences; Physiological aspects; Podocytes - cytology; Podocytes - metabolism; Signal transduction; Telomerase; Telomerase - genetics; Telomerase - metabolism; Tumors; Wnt Signaling Pathway; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2550

Steven Artandi and his colleagues have found that dedifferentiation and proliferation of kidney podocytes as a result of TERT or Wnt signaling leads to a collapsing glomerulopathy phenotype in mice, similar to that seen in HIV-associated nephropathy (HIVAN) in humans, and that inhibiting these pathways corrected disease progression. They also found that TERT expression and Wnt activity is elevated in a mouse model of HIVAN and in human HIVAN renal samples, suggesting possible targets to treat this disease.
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.