The WT1 Interacting Protein: A molecular messenger between the slit diaphragm and podocyte nucleus

Abstract

Podocyte differentiation is critical for glomerular filtration barrier function, which is regulated by WT1, a zinc finger transcription factor. We identified a novel protein called the WT1 interacting protein (WTIP) and propose that WTIP normally monitors slit diaphragm assembly and shuttles into the nucleus after podocyte injury. To investigate nucleocytoplasmic translocation, podocytes that stably express an inducible, epitope‐tagged WTIP were treated with LPS, which causes transient nephrotic syndrome in mice. WTIP rapidly disassembles from cell‐contacts, transits along cytoskeletal‐based structures, localizes in podocyte nuclei by 6 hrs but shifts back to plasma membrane after 24 hrs. LPS stimulates podocyte JNK activity in a time‐dependent manner, and a JNK, but not p38 inhibitor, prevents translocation of WTIP to nuclei. Intact actin cytoskeleton and microtubular networks, as well as activity of the motor protein, dynein, are required for LPS‐stimulated WTIP translocation. We propose WTIP translocation to nucleus requires an intricate orchestration of JNK activation, which releases WTIP from podocyte cell contacts and promotes assembly of a dynein‐based complex that transports WTIP to the nucleus for import. Nuclear WTIP may reprogram WT1‐dependent gene expression to facilitate a podocyte phenotype switch that promotes cell survival until an injury is terminated.