Kidney Week

Abstract: FR-PO753

Mathematical Modeling of Podocyte Adhesion Highlights the Role of Cell Contractility and Fluid Shear Stress on Kidney Function

Session Information

• Glomerular Diseases: Mechanisms and Podocyte Biology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Jiang, Shumeng, Washington University in St Louis, St Louis, Missouri, United States

Shumeng Jiang, PhD

• Puapatanakul, Pongpratch, Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Pongpratch Puapatanakul, MD, MS, MSc

• Qu, Chengqing, Washington University in St Louis, St Louis, Missouri, United States

Chengqing Qu

• Langner, Ewa, Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Ewa Langner, PhD

• Mahjoub, Moe, Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Moe Mahjoub, PhD

• Miner, Jeffrey H., Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Jeffrey H. Miner, PhD, FASN

• Genin, Guy M., Washington University in St Louis, St Louis, Missouri, United States

Guy M. Genin, PhD

• Suleiman, Hani, Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Hani Suleiman, MD, PhD

Background

Diseases of the kidney’s glomerular filtration barrier can lead to podocyte detachment, which impairs filtration and ultimately leads to end-stage kidney disease. However, the mechanisms responsible for securing podocyte attachment to the glomerular basement membrane (GBM), as well as how these malfunctions in pathological conditions, are not fully understood.

Methods

In order to predict the stability of podocyte attachment, we developed a mathematical model of the actin cytoskeleton in podocyte foot processes and their connections to the GBM. This model considers forces from filtration shear and cell contraction, and their impact on the stability of integrin bonds that connect foot processes to the GBM.

Results

Our modeling reveals that specific integrin patterning in the foot processes and a balance between extrinsic and intrinsic stresses play a crucial role in maintaining stable attachment of podocytes. These findings were further supported by a new mouse model with controllable glomerular filtration rate (GFR) and cell contractility. The use of expansion microscopy (ExM) and super-resolution imaging confirmed the predicted integrin patterns, while assessments of kidney injury validated our predictions regarding the stability of podocyte attachment under varying environmental forces.

Conclusion

Our simulations and mouse model verifications emphasize the significance of mechanical stresses, specifically cell contractility and fluid shear stress, in maintaining glomerular filtration function. This insight presents new therapeutic opportunities for chronic kidney diseases by manipulating these mechanical cues.

Funding

• NIDDK Support