Similar biophysical abnormalities in glomeruli and podocytes from two distinct models

Addie E. Embry, Zhenan Liu, Joel M. Henderson, F. Jefferson Byfield, Liping Liu, Joonho Yoon, Zhenzhen Wu, Katrina Cruz, Sara Moradi, C. Barton Gillombardo, Rihanna Z. Hussain, Richard Doelger, Olaf Stuve, Audrey N. Chang, Paul A. Janmey, Leslie A. Bruggeman, R. Tyler Miller

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Abstract

Background FSGS is a pattern of podocyte injury that leads to loss of glomerular function. Podocytes support other podocytes and glomerular capillary structure, oppose hemodynamic forces, form the slit diaphragm, and have mechanical properties that permit these functions. However, the biophysical characteristics of glomeruli and podocytes in disease remain unclear. Methods Using microindentation, atomic force microscopy, immunofluorescence microscopy, quantitative RT-PCR, and a three-dimensional collagen gel contraction assay, we studied the biophysical and structural properties of glomeruli and podocytes in chronic (Tg26mice [HIV protein expression]) and acute (protamine administration [cytoskeletal rearrangement]) models of podocyte injury. Results Compared with wild-type glomeruli, Tg26 glomeruli became progressivelymore deformable with disease progression, despite increased collagen content. Tg26 podocytes had disordered cytoskeletons, markedly abnormal focal adhesions, and weaker adhesion; they failed to respond to mechanical signals and exerted minimal traction force in three-dimensional collagen gels. Protamine treatment had similar but milder effects on glomeruli and podocytes. Conclusions Reduced structural integrity of Tg26 podocytes causes increased deformability of glomerular capillaries and limits the ability of capillaries to counter hemodynamic force, possibly leading to further podocyte injury. Loss of normal podocytemechanical integrity could injure neighboring podocytes due to the absence of normal biophysical signals required for podocyte maintenance. The severe defects in podocyte mechanical behavior in the Tg26 model may explain why Tg26 glomeruli soften progressively, despite increased collagen deposition, and may be the basis for the rapid course of glomerular diseases associated with severe podocyte injury. In milder injury (protamine), similar processes occur but over a longer time.

Original languageEnglish (US)
Pages (from-to)1501-1512
Number of pages12
JournalJournal of the American Society of Nephrology
Volume29
Issue number5
DOIs
StatePublished - May 2018

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ASJC Scopus subject areas

  • Nephrology

Cite this

Embry, A. E., Liu, Z., Henderson, J. M., Byfield, F. J., Liu, L., Yoon, J., Wu, Z., Cruz, K., Moradi, S., Gillombardo, C. B., Hussain, R. Z., Doelger, R., Stuve, O., Chang, A. N., Janmey, P. A., Bruggeman, L. A., & Miller, R. T. (2018). Similar biophysical abnormalities in glomeruli and podocytes from two distinct models. Journal of the American Society of Nephrology, 29(5), 1501-1512. https://doi.org/10.1681/ASN.2017050475