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Abstract: FR-PO700

Sarcomere-Like Structures Prevent Podocyte Detachment and Template Synaptopodin-Positive Extensions

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Jiang, Shumeng, Washington University in St Louis, St Louis, Missouri, United States
  • Miner, Jeffrey H., Washington University in St Louis School of Medicine, St Louis, Missouri, United States
  • Genin, Guy M., Washington University in St Louis, St Louis, Missouri, United States
  • Suleiman, Hani, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
Background

Podocyte injuries can cause chronic kidney disease, which is widespread and incurable. The biophysical mechanisms underlying podocyte responses to injury are unclear, in part because materials systems for mimicking the microenvironment of relevant kidney cells are limited.

Methods

We developed an ex vivo micropatterned hydrogel culture system that allows the control of the podocyte microenvironment, including ECM substrate types, stiffness, and cell shapes. This approach allows us to study the primary podocyte cytoskeleton immediately after their migration from isolated glomeruli of both mouse and human origins.

Results

In this culture system, primary podocytes upregulated a mat of sarcomere-like structures (SLSs), with striations composed of alternating clusters of α-actinin 4, synaptopodin and myosin IIA in the early stages of spreading. These structures are reminiscent of the SLSs observed in pathological podocytes in vivo. The periodic synaptopodin-positive clusters nucleated peripheral, foot process-like extensions, suggesting a role for SLSs in guiding the formation and proper spacing of these processes. SLSs were not found in a podocyte cell line, either before or after differentiation.
Functionally, podocytes presenting SLSs were highly contractile. The SLSs were dissembled when we reduced their contractility either by inhibiting myosin, decreasing substrate stiffness, or inhibiting RhoA, ROCK or formins to target the Rho signaling pathway. In addition, our experiments revealed faster detachment of podocytes that lost SLSs, emphasizing the need for SLSs in injured podocytes to prevent podocyte loss as part of an adaptive mechanism after injury.

Conclusion

We show that SLSs may have a dual role in podocyte biology: providing sufficient contractility that helps maintain adhesion to the GBM after injury; and templating the formation of foot process in immature podocytes or those recovering from injury. Therefore, the SLSs in injured podocytes may serve as potential therapeutic targets.

Funding

  • NIDDK Support