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

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.

Biomechanical Evaluation of Lumbar Decompression Adjacent to Instrumented Segments.

BACKGROUND: Multilevel lumbar stenosis, in which 1 level requires stabilization due to spondylolisthesis, is routinely treated with multilevel open laminectomy and fusion. We hypothesized that a minimally invasive (MI) decompression is biomechanically superior to open laminectomy and may allow decompression of the level adjacent the spondylolisthesis without additional fusion. OBJECTIVE: To study the mechanical effect of various decompression procedures adjacent to instrumented segments in cadaver lumbar spines. METHODS: Conditions tested were (1) L4-L5 instrumentation, (2) L3-L4 MI decompression, (3) addition of partial facetectomy at L3-L4, and (4) addition of laminectomy at L3-L4. Flexibility tests were performed for range of motion (ROM) analysis by applying nonconstraining, pure moment loading during flexion-extension, lateral bending, and axial rotation. Compression flexion tests were performed for motion distribution analysis. RESULTS: After instrumentation, MI decompression increased flexion-extension ROM at L3-L4 by 13% (P = .03) and axial rotation by 23% (P = .003). Partial facetectomy further increased axial rotation by 15% (P = .03). After laminectomy, flexion-extension ROM further increased by 12% (P = .05), a 38% increase from baseline, and axial rotation by 17% (P = .02), a 58% increase from baseline. MI decompression yielded no significant increase in segmental contribution of motion at L3-L4, in contrast to partial facetectomy and laminectomy (<.05). CONCLUSION: MI tubular decompression is biomechanically superior to open laminectomy adjacent to instrumented segments. These results lend support to the concept that in patients in whom a multilevel MI decompression is performed, the fusion might be limited to the segments with actual instability. ABBREVIATION: MI, minimally invasive.

Minimally Invasive Approach For Extraforaminal Synovial Cyst L5-S1.

Symptoms from synovial cysts are produced by neural compression in the spinal canal or the foramen. Few cases of extraforaminal synovial cyst have been published in the literature. This is a case report of a 65-year-old female who presented with a three-month history of sciatic pain and no relief with conservative treatment. MRI showed a left-sided extraforaminal synovial cyst at L5-S1 with compression of the L5 nerve root at the lateral portion of the foramen. Minimally invasive surgery for resection was performed using an extraforaminal tubular microscopic endoscopy-assisted approach. The patient improved clinically and remained symptom-free for the entire follow-up of 30 months.

Riboflavin crosslinked high-density collagen gel for the repair of annular defects in intervertebral discs: An in vivo study.

Open annular defects compromise the ability of the annulus fibrosus to contain nuclear tissue in the disc space, and therefore lead to disc herniation with subsequent degenerative changes to the entire intervertebral disc. This study reports the use of riboflavin crosslinked high-density collagen gel for the repair of annular defects in a needle-punctured rat-tail model. High-density collagen has increased stiffness and greater hydraulic permeability than conventional low-density gels; riboflavin crosslinking further increases these properties. This study found that treating annular defects with crosslinked high-density collagen inhibited the progression of disc degeneration over 18 weeks compared to untreated control discs. Histological sections of FITC-labeled collagen gel revealed an early tight attachment to host annular tissue. The gel was subsequently infiltrated by host fibroblasts which remodeled it into a fibrous cap that bridged the outer disrupted annular fibers and partially repaired the defect. This repair tissue enhanced retention of nucleus pulposus tissue, maintained physiological disc hydration, and preserved hydraulic permeability, according to MRI, histological, and mechanical assessments. Degenerative changes were partially reversed in treated discs, as indicated by an increase in nucleus pulposus size and hydration between weeks 5 and 18. The collagen gel appeared to work as an instant sealant and by enhancing the intrinsic healing capabilities of the host tissue.