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Biophysical properties of normal and diseased renal glomeruli
journal contributionposted on 2015-06-11, 15:20 authored by Hans M. Wyss, Joel M. Henderson, Fitzroy J. Byfield, Leslie A. Bruggeman, Yaxian Ding, Chunfa Huang, Jung Hee Suh, Thomas Franke, Elisa MeleElisa Mele, Martin R. Pollak, Jeffrey H. Miner, Paul A. Janmey, David A. Weitz, R. Tyler Miller
The mechanical properties of tissues and cells including renal glomeruli are important determinants of their differentiated state, function, and responses to injury but are not well characterized or understood. Understanding glomerular mechanics is important for understanding renal diseases attributable to abnormal expression or assembly of structural proteins and abnormal hemodynamics. We use atomic force microscopy (AFM) and a new technique, capillary micromechanics, to measure the elastic properties of rat glomeruli. The Young's modulus of glomeruli was 2,500 Pa, and it was reduced to 1,100 Pa by cytochalasin and latunculin, and to 1,400 Pa by blebbistatin. Cytochalasin or latrunculin reduced the F/G actin ratios of glomeruli but did not disrupt their architecture. To assess glomerular biomechanics in disease, we measured the Young's moduli of glomeruli from two mouse models of primary glomerular disease, Col4a3−/− mice (Alport model) and Tg26HIV/nl mice (HIV-associated nephropathy model), at stages where glomerular injury was minimal by histopathology. Col4a3−/− mice express abnormal glomerular basement membrane proteins, and Tg26HIV/nl mouse podocytes have multiple abnormalities in morphology, adhesion, and cytoskeletal structure. In both models, the Young's modulus of the glomeruli was reduced by 30%. We find that glomeruli have specific and quantifiable biomechanical properties that are dependent on the state of the actin cytoskeleton and nonmuscle myosins. These properties may be altered early in disease and represent an important early component of disease. This increased deformability of glomeruli could directly contribute to disease by permitting increased distension with hemodynamic force or represent a mechanically inhospitable environment for glomerular cells.
This work was supported by a Veterans Affairs Mertit Review award to R. T. Miller, the Leonard Rosenberg Research and Education Foundation, the Rammelkamp Center for Research and Education, and awards from the NIH (RO1DK-083592 to L. A. Bruggeman, J. M. Henderson, P. A. Janmey, R. T. Miller, M. R. Pollak, and D. A. Weitz; DK-59588 to M. R. Pollak, K08-DK- 073091 to J. M. Henderson, and R01DK-078314 to J. H. Miner), the NSF to D. A. Weitz (DMR-1006546) and the Harvard MRSEC to D. A. Weitz (DMR-0820484).
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