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

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 critical for filtration – are thought to lack significant capacity for regeneration. Here, we show that podocytes rapidly lose differentiation markers and enter cell cycle in adult mice in which the telomerase protein component TERT is conditionally expressed. Transgenic TERT expression induces marked upregulation of Wnt signaling and disrupts glomerular structure resulting in a collapsing glomerulopathy resembling those in humans, including HIV-associated nephropathy (HIVAN). Human and mouse HIVAN kidneys show increased levels of TERT and activation of Wnt signaling, indicating that these are general features of collapsing glomerulopathies. Either silencing transgenic TERT expression or inhibition of Wnt signaling through systemic expression of the Wnt-inhibitor Dkk1 in TERT transgenic mice 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 property of podocytes to reversibly enter 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.