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Abstract: FR-PO206

Diabetic Nephropathy Is Associated with Reduced Fraction of Glomerular Basement Membrane Surface Area Opening into the Subpodocyte Space

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Sargolzaeiaval, Forough, University of Washington, Seattle, Washington, United States
  • Farkash, Roni, University of Washington, Seattle, Washington, United States
  • Mauer, Michael, University of Minnesota, Minneapolis, Minnesota, United States
  • Nelson, Robert G., National Institutes of Health, Phoenix, Arizona, United States
  • Najafian, Behzad, University of Washington, Seattle, Washington, United States
Background

Diabetic nephropathy (DN) is the leading cause of end stage kidney disease in the US and better understanding of mechanisms of kidney dysfunction in DN is needed. Current structural functional relationship models, including classical lesions are poor predictors of GFR decline, these imply the possible role of other factors involved in DN progression. Subpodocyte space (SPS) defined as the space between interdigitating foot processes covering GBM and the bottom surface of cell bodies has been characterized through serial sectioning and electron microscopy studies. The SPS is able to retain macromolecules and act as a resistance to fluid flow. However, knowledge about this space is very limited due to lack of validated methodologies for quantification of SPS properties. We developed unbiased quantitative approaches to quantify SPS properties using transmission electron microscopy and validated using SBF-SEM and 3D modeling. Our study will provide an approach to understand how SPS interplays with other structural changes in affecting kidney dysfunction in DN.

Methods

9 Kidney biopsies of type 2 diabetes were selected and the results were compared with 5 normal controls. Structural studies were performed using these approaches: (1) segmentation of urinary spaces and identification of exit pores; (2) quantification of surface fraction and total surface of GBM opening into SPS/IPS/PUS and volumes of those spaces; (3) quantification of average in-flow areas and out-flow areas of SPS/IPS/PUS and lengths of outflow areas of those spaces

Results

Comparison of glomeruli from 9 T2D patients and 5 normal controls showed classical changes of DN. While the volume and the GBM surface exposed to each of the urinary space compartments were increased in DN, surface density of SPS and IPS were reduced and this reduction was more prominent for SPS (over 2 folds) . Moreover, in DN patients, %GBM surface which is exposed to SPS was reduced and, in contrast, %GBM exposed to IPS was increased (P=0.001). The data indicates significant reduction in in-flow and widening of out-flow areas in DN compared to control (P<0.05).

Conclusion

Structural properties of urinary spaces are differentially regulated and reduced %GBM exposed to SPS may be a compensatory mechanism against GFR loss in DN.

Funding

  • NIDDK Support