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Abstract: FR-PO733

The Role of Combinatorial Inflammatory and Senescence-Associated Secretory Phenotype (SASP) Signaling Pathways in Podocyte Aging

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

  • Sharara, Jana, Cleveland Clinic, Cleveland, Ohio, United States
  • Pippin, Jeffrey W., University of Washington, Seattle, Washington, United States
  • Zarouk, Alexander A., Cleveland Clinic, Cleveland, Ohio, United States
  • Tran, Uyen, Cleveland Clinic, Cleveland, Ohio, United States
  • Shankland, Stuart J., University of Washington, Seattle, Washington, United States
  • Wessely, Oliver, Cleveland Clinic, Cleveland, Ohio, United States
Background

Podocytes play a pivotal role in maintaining the integrity and function of the glomerular filtration barrier. In the aged kidney, podocytes undergo shortened lifespan and reduced health-span, characterized by altered morphology, decreased cellular proliferation, and impaired function. This age-associated podocyte senescence could contribute to the decline in renal function observed in elderly individuals and increase susceptibility to various renal pathologies. Previous findings show that multiple inflammatory and senescence-associated secretory phenotype (SASP) pathways are upregulated in aged and injured podocytes. We hypothesize that these pathways contribute to decline in podocyte function via autocrine and paracrine signaling.

Methods

To investigate the numerous inflammatory and SASP pathways upregulated in podocyte aging/injury, a classic one-factor-at-a-time approach which tests each pathway individually is impractical and also does not consider synergistic interactions. To holistically address the complexity of the aging and injury secretome, our study implements a Design-of-Experiment (DoE) approach. In this approach, all inflammatory and SASP pathways are altered simultaneously through computer-generated experiments to obtain optimal results and quality. This allows us to directly identify which specific combination of inflammatory cytokines and SASP proteins secreted from aged/injured podocytes are causally involved in altered podocyte function.

Results

We performed DoE approaches in well-characterized young and aged primary mouse podocytes. We interrogated 13 different antagonists to various inflammatory and SASP pathways and studied two outcomes, apoptosis and senescence. The DOE identified pathways with the most robust pro- and anti-aging and injury responses. These specific combinations were then characterized and analyzed, using a more traditional approach by assessing the inflammatory/aging phenotype with mRNAseq, qPCR, and immunohistochemistry.

Conclusion

The DoE approach provides a comprehensive understanding of the interplay between inflammatory and SASP pathways in podocyte aging and disease. It offers potential targets for therapeutic intervention that may lead to the development of novel treatments to preserve kidney function in the elderly.

Funding

  • NIDDK Support