Dataset Information

Nebulette reinforces podocyte structural integrity by linking actin and vimentin filaments

ABSTRACT: One of the key aspects of the specialized podocyte morphology is the segregation and organization of distinct cytoskeletal filaments into different subcellular components, for which the exact mechanisms remain poorly understood. By screening the time-dependent proteomic changes within the rat puromycin aminonucleoside-induced nephropathy model, we identify the actin-binding protein nebulette as a unique component of the podocyte cytoskeleton that correlates strongly with glomerular function.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Podocyte (sensu Diptera), Kidney

DISEASE(S): Disease Free

SUBMITTER: Tong Liu

LAB HEAD: Evren U. Azeloglu

PROVIDER: PXD016629 | Pride | 2022-02-15

REPOSITORIES: pride

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LIM-Nebulette Reinforces Podocyte Structural Integrity by Linking Actin and Vimentin Filaments.

Ge Xuhua X Zhang Tao T Yu Xiaoxia X Muwonge Alecia N AN Anandakrishnan Nanditha N Wong Nicholas J NJ Haydak Jonathan C JC Reid Jordan M JM Fu Jia J Wong Jenny S JS Bhattacharya Smiti S Cuttitta Christina M CM Zhong Fang F Gordon Ronald E RE Salem Fadi F Janssen William W Hone James C JC Zhang Aihua A Li Hong H He John C JC Gusella G Luca GL Campbell Kirk N KN Azeloglu Evren U EU

Journal of the American Society of Nephrology : JASN 20200731 10

<h4>Background</h4>Maintenance of the intricate interdigitating morphology of podocytes is crucial for glomerular filtration. One of the key aspects of specialized podocyte morphology is the segregation and organization of distinct cytoskeletal filaments into different subcellular components, for which the exact mechanisms remain poorly understood.<h4>Methods</h4>Cells from rats, mice, and humans were used to describe the cytoskeletal configuration underlying podocyte structure. Screening the ti ...[more]

PMID: 32737144

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Project description:BackgroundMaintenance of the intricate interdigitating morphology of podocytes is crucial for glomerular filtration. One of the key aspects of specialized podocyte morphology is the segregation and organization of distinct cytoskeletal filaments into different subcellular components, for which the exact mechanisms remain poorly understood.MethodsCells from rats, mice, and humans were used to describe the cytoskeletal configuration underlying podocyte structure. Screening the time-dependent proteomic changes in the rat puromycin aminonucleoside-induced nephropathy model correlated the actin-binding protein LIM-nebulette strongly with glomerular function. Single-cell RNA sequencing and immunogold labeling were used to determine Nebl expression specificity in podocytes. Automated high-content imaging, super-resolution microscopy, atomic force microscopy (AFM), live-cell imaging of calcium, and measurement of motility and adhesion dynamics characterized the physiologic role of LIM-nebulette in podocytes.ResultsNebl knockout mice have increased susceptibility to adriamycin-induced nephropathy and display morphologic, cytoskeletal, and focal adhesion abnormalities with altered calcium dynamics, motility, and Rho GTPase activity. LIM-nebulette expression is decreased in diabetic nephropathy and FSGS patients at both the transcript and protein level. In mice, rats, and humans, LIM-nebulette expression is localized to primary, secondary, and tertiary processes of podocytes, where it colocalizes with focal adhesions as well as with vimentin fibers. LIM-nebulette shRNA knockdown in immortalized human podocytes leads to dysregulation of vimentin filament organization and reduced cellular elasticity as measured by AFM indentation.ConclusionsLIM-nebulette is a multifunctional cytoskeletal protein that is critical in the maintenance of podocyte structural integrity through active reorganization of focal adhesions, the actin cytoskeleton, and intermediate filaments.

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