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Abstract: TH-PO975

p90RSK Modulates Fibroblast-Epithelial Communication

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Shi, Chaowen, Penn State University College of Medicine, Hershey, Pennsylvania, United States
  • Lin, Ling, Penn State University College of Medicine, Hershey, Pennsylvania, United States
  • Hu, Kebin, Penn State University College of Medicine, Hershey, Pennsylvania, United States
Background

Tubular epithelial damage is one of the prominent hallmarks of both acute and chronic kidney injury. Emerging evidence illuminates the fundamental role of intercellular communication in maintaining the integrity of kidney structure and environment. P90RSK is a serine/threonine kinase induced in the fibrotic kidneys. However, its role in kidney fibrosis remains unknown.

Methods

We examined p90RSK activation in human kidney samples. We generated a novel fibroblast-specific p90RSK transgenic mouse (RSK-Tg) and established a fibroblast-epitheial coculture system using primary kidney fibroblasts from RSK-Tg and RSK-wt mice and human proximal tubular epithelial cells (HKC-8) to investigate the role of p90RSK in fibroblast-epitheial interactions

Results

We discoved that p90RSK phosphorylation was increased in the kidney samples from patients with chronic kidney disease. We also found that RSK-Tg mice displayed enhanced renal fibrosis and increased tubular epithelial cell death after obstructive injury than their littermates (RSK-wt), indicating a role of p90RSK in fibroblast-epithelial communication. We established an in vitro fibroblast-epithelial coculture system using primary kidney fibroblasts from RSK-Tg and RSK-wt mice and human proximal tubular epithelial cells (HKC-8), and found that RSK-Tg fibroblasts dramatically aggregated staurosporine or H2O2-induced epithelial apoptosis. We further discovered that RSK-Tg fibroblasts constantly produced and released higher level of H2O2 into the coculture medium causing epithelial oxidative stress and nuclear translocation of β-catenin. Intriguingly, blockade of reactive oxygen species (ROS) reduced RSK-Tg fibroblasts-induced β-catenin and epithelial apoptosis. Moreover, knockdown of β-catenin by RNA silencing eliminated RSK-Tg fibroblast-induced epithelial cell death.

Conclusion

Thus, it is clear that fibroblast-p90RSK mediates epithelial cell death through ROS-activated β-catenin pathway.

Funding

  • NIDDK Support