1. The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics.
- Author
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Meliambro K, Wong JS, Ray J, Calizo RC, Towne S, Cole B, El Salem F, Gordon RE, Kaufman L, He JC, Azeloglu EU, and Campbell KN
- Subjects
- Animals, Biopsy, Female, Gene Expression Regulation, Glomerulosclerosis, Focal Segmental enzymology, Glomerulosclerosis, Focal Segmental pathology, HEK293 Cells, Hippo Signaling Pathway, Humans, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins genetics, Male, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Phosphoproteins antagonists & inhibitors, Phosphoproteins genetics, Phosphorylation, Podocytes pathology, Podocytes ultrastructure, Protein Processing, Post-Translational, RNA Interference, Serine metabolism, Transcription Factors, YAP-Signaling Proteins, Actin Cytoskeleton metabolism, Adaptor Proteins, Signal Transducing metabolism, Glomerulosclerosis, Focal Segmental metabolism, Intracellular Signaling Peptides and Proteins metabolism, Phosphoproteins metabolism, Podocytes metabolism, Protein Serine-Threonine Kinases metabolism, Signal Transduction
- Abstract
Kidney podocytes represent a key constituent of the glomerular filtration barrier. Identifying the molecular mechanisms of podocyte injury and survival is important for better understanding and management of kidney diseases. KIBRA ( ki dney bra in protein), an upstream regulator of the Hippo signaling pathway encoded by the Wwc1 gene, shares the pro-injury properties of its putative binding partner dendrin and antagonizes the pro-survival signaling of the downstream Hippo pathway effector YAP (Yes-associated protein) in Drosophila and MCF10A cells. We recently identified YAP as an essential component of the glomerular filtration barrier that promotes podocyte survival by inhibiting dendrin pro-apoptotic function. Despite these recent advances, the signaling pathways that mediate podocyte injury remain poorly understood. Here we tested the hypothesis that, similar to its role in other model systems, KIBRA promotes podocyte injury. We found increased expression of KIBRA and phosphorylated YAP protein in glomeruli of patients with biopsy-proven focal segmental glomerulosclerosis (FSGS). KIBRA/ WWc1 overexpression in murine podocytes promoted LATS kinase phosphorylation, leading to subsequent YAP Ser-127 phosphorylation, YAP cytoplasmic sequestration, and reduction in YAP target gene expression. Functionally, KIBRA overexpression induced significant morphological changes in podocytes, including disruption of the actin cytoskeletal architecture and reduction of focal adhesion size and number, all of which were rescued by subsequent YAP overexpression. Conversely, constitutive KIBRA knockout mice displayed reduced phosphorylated YAP and increased YAP expression at baseline. These mice were protected from acute podocyte foot process effacement following protamine sulfate perfusion. KIBRA knockdown podocytes were also protected against protamine-induced injury. These findings suggest an important role for KIBRA in the pathogenesis of podocyte injury and the progression of proteinuric kidney disease., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2017
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