Similar Biophysical Abnormalities in Glomeruli and Podocytes from Two Distinct Models.

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 (Tg26 mice [HIV protein expression]) and acute (protamine administration [cytoskeletal rearrangement]) models of podocyte injury.Results Compared with wild-type glomeruli, Tg26 glomeruli became progressively more 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 podocyte mechanical 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.

• Authors: 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
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 29 Issue 5 Pg. 1501-1512 (05 2018) ISSN: 1533-3450 [Electronic] United States
• PMID: 29572404 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society of Nephrology.

Chemical References

• Paxillin
• Protamines
• Collagen

Topics

• Animals
• Biophysical Phenomena
• Cell Adhesion
• Collagen (metabolism)
• Cytoskeleton (physiology)
• Disease Models, Animal
• Disease Progression
• Elastic Modulus
• Glomerulonephritis (genetics, pathology, physiopathology)
• HIV (genetics)
• Kidney Glomerulus (pathology, physiopathology)
• Mice
• Mice, Transgenic
• Microscopy, Atomic Force
• Microscopy, Fluorescence
• Nephrosis, Lipoid (chemically induced, pathology, physiopathology)
• Paxillin (metabolism)
• Podocytes (pathology, physiology)
• Protamines
• Real-Time Polymerase Chain Reaction