The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics

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 (dney in protein), an upstream regulator of the Hippo signaling pathway encoded by the 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 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/ 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.

Nuclear YAP localization as a key regulator of podocyte function

“…The observations that (i) podocyte-specific YAP deletion in mice results in FSGS and (ii) the amount of p-YAP increases in human FSGS give a hint that Hippo pathway activation is linked to FSGS development 8 . Therefore, we compared the dataset from our transcriptome analysis with the data from two independent studies of transcriptional regulation in glomeruli from human FSGS patients (transcriptomic datasets from Hodgin et al 27 and Ju et al 28 ) obtained from the Nephroseq database ( www.nephroseq.org ).…”

“…In mice, podocyte-specific YAP deletion results in podocyte depletion, proteinuria, and focal segmental glomerulosclerosis (FSGS) 5 . Human FSGS patients show an increased phosphorylation of YAP (p-YAP), which is equivalent to YAP inactivation 8 . However, the changes in podocyte gene transcription after Hippo signaling activation and the role of LATS kinases in this process remained unclear.…”

Similar Biophysical Abnormalities in Glomeruli and Podocytes from Two Distinct Models

“…30,31 Additionally, mRNA for proteins associated with cells' mechanical environment (filamin A and nonmuscle myosin IIa), 14,32 genes that increase with fibrosis and are used as markers for myofibroblast development (desmin and a-smooth muscle actin), and proteins associated with mechanosensing and fibrosis (YAP and TAZ) are reduced in Tg26 podocytes and stage 2 glomeruli (Supplemental Figure 2). [33][34][35] These results show that Tg26 podocytes have not only abnormal morphology Paired responses to matrix stiffness are compared to illustrate a broader dynamic range of cytoskeletal rearrangement in the WT. (D) Comparison of WT and Tg26 podocyte cell morphology changes in response to matrix stiffness.…”

Distinctive phosphoinositide- and Ca2+-binding properties of normal and cognitive performance–linked variant forms of KIBRA C2 domain

“…1). KIBRA has about 20 reported binding partners (2) and disease links, including dementia (3)(4)(5), kidney disease (6), Tourette disorder (7), and some cancers (8,9). Among its multiple functions, KIBRA is an upstream component of the Hippo pathway (8,10), a central mechanism of organ size control and cellular homeostasis.…”