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

Xuhua Ge, Tao Zhang, Xiaoxia Yu, Alecia N. Muwonge, Nanditha Anandakrishnan, Nicholas J. Wong, Jonathan C. Haydak, Jordan M. Reid, Jia Fu, Jenny S. Wong, Smiti Bhattacharya, Christina M. Cuttitta, Fang Zhong, Ronald E. Gordon, Fadi Salem, William Janssen, James C. Hone, Aihua Zhang, Hong Li, John C. He, G. Luca Gusella, Kirk N. Campbell and Evren U. Azeloglu
JASN October 2020, 31 (10) 2372-2391; DOI: https://doi.org/10.1681/ASN.2019121261
Xuhua Ge
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Tao Zhang
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Xiaoxia Yu
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Alecia N. Muwonge
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Nanditha Anandakrishnan
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Nicholas J. Wong
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Jonathan C. Haydak
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Jordan M. Reid
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Jia Fu
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Jenny S. Wong
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Smiti Bhattacharya
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
2Department of Mechanical Engineering, Columbia University, New York, New York
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Christina M. Cuttitta
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Fang Zhong
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Ronald E. Gordon
3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York
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Fadi Salem
3Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York
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William Janssen
4Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
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James C. Hone
2Department of Mechanical Engineering, Columbia University, New York, New York
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Aihua Zhang
5Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
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Hong Li
6Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University–New Jersey Medical School, Newark, New Jersey
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John C. He
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
7Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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G. Luca Gusella
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Kirk N. Campbell
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Evren U. Azeloglu
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
7Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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Visual Abstract

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Significance Statement

The functional basis of the spatial cytoskeletal organization in the kidney podocyte that gives rise to its unique interdigitating morphology has been elusive. An integrative approach identified a novel podocyte-specific actin-associated protein, LIM-nebulette, that brings vimentin intermediate filaments to actin microfilaments, promoting mechanical stability, by regulating focal adhesions, calcium dynamics, and Rho GTPase activity. Silencing of LIM-nebulette is associated with aberrant biophysical properties in human podocytes in culture as well as with multiple glomerulopathies in patients, at both the RNA transcript and protein levels.

Abstract

Background 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.

Methods Cells 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.

Results Nebl 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.

Conclusions LIM-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.

  • podocyte
  • cell adhesion
  • cytoskeleton
  • microscopy
  • proteomics
  • glomerulus
  • Copyright © 2020 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 31 (10)
Journal of the American Society of Nephrology
Vol. 31, Issue 10
October 2020
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LIM-Nebulette Reinforces Podocyte Structural Integrity by Linking Actin and Vimentin Filaments
Xuhua Ge, Tao Zhang, Xiaoxia Yu, Alecia N. Muwonge, Nanditha Anandakrishnan, Nicholas J. Wong, Jonathan C. Haydak, Jordan M. Reid, Jia Fu, Jenny S. Wong, Smiti Bhattacharya, Christina M. Cuttitta, Fang Zhong, Ronald E. Gordon, Fadi Salem, William Janssen, James C. Hone, Aihua Zhang, Hong Li, John C. He, G. Luca Gusella, Kirk N. Campbell, Evren U. Azeloglu
JASN Oct 2020, 31 (10) 2372-2391; DOI: 10.1681/ASN.2019121261

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LIM-Nebulette Reinforces Podocyte Structural Integrity by Linking Actin and Vimentin Filaments
Xuhua Ge, Tao Zhang, Xiaoxia Yu, Alecia N. Muwonge, Nanditha Anandakrishnan, Nicholas J. Wong, Jonathan C. Haydak, Jordan M. Reid, Jia Fu, Jenny S. Wong, Smiti Bhattacharya, Christina M. Cuttitta, Fang Zhong, Ronald E. Gordon, Fadi Salem, William Janssen, James C. Hone, Aihua Zhang, Hong Li, John C. He, G. Luca Gusella, Kirk N. Campbell, Evren U. Azeloglu
JASN Oct 2020, 31 (10) 2372-2391; DOI: 10.1681/ASN.2019121261
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Keywords

  • podocyte
  • cell adhesion
  • cytoskeleton
  • microscopy
  • proteomics
  • glomerulus

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