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 (kidney brain 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.
Highlights
These data suggest an association between increased KIBRA glomerular expression and human podocytopathy that may be mediated by increases in Yes-associated protein (YAP) phosphorylation
We have demonstrated that increased KIBRA expression in the podocyte is associated with human focal segmental glomerulosclerosis (FSGS)
KIBRA promoted LATS phosphorylation resulting in YAP phosphorylation, cytoplasmic sequestration, and inactivation, characterized by decreased target gene expression
Summary
FSGS, a human podocytopathy, is increasing in prevalence worldwide for unclear reasons and is the most common primary glomerular disease leading to end-stage kidney disease in the United States [25,26,27]. Given that KIBRA was recently shown to increase P-YAP expression in human podocytes in vitro [28], we quantified P-YAP expression in FSGS glomeruli and found it to be significantly higher (p Ͻ 0.005) compared with normal glomeruli (Fig. 1, A and B). Consistent with published data, synaptopodin expression in these unscarred glomerular segments was decreased compared with normal glomeruli [31] These data suggest an association between increased KIBRA glomerular expression and human podocytopathy that may be mediated by increases in YAP phosphorylation. Following PS perfusion, WT mice had increased foot process effacement compared with KIBRA/Wwc1-KO littermates (Fig. 8B, right panels) Quantification of this observation confirmed that after PS perfusion, Wwc1-KO mice did not have a significant decrease in the number of FPs per glomerular basement membrane (GBM) length. These data show that KIBRA silencing protects podocytes from actin cytoskeletal injury using both in vivo and in vitro models
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
