Abstract: FR-PO363
Fibroblast-Specific p90RSK Promotes Kidney Fibrosis
Session Information
- Mechanisms Associated with Kidney Fibrosis - I
November 03, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Chronic Kidney Disease (Non-Dialysis)
- 308 CKD: Mechanisms of Tubulointerstitial Fibrosis
Authors
- Lin, Ling, Penn State University College of Medicine, Hershey, Pennsylvania, United States
- Shi, Chaowen, Penn State University College of Medicine, Hershey, Pennsylvania, United States
- Hu, Kebin, Penn State University College of Medicine, Hershey, Pennsylvania, United States
Background
The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases that regulate diverse cellular process, such as cell growth, cell motility, and cell survival. There are 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK and predominantly expressed in the kidney. p90RSK is recently shown to promote diabetic endothelial dysfunction and atherosclerosis, however, the role of p90RSK in the development and progression of chronic kidney disease has never been investigated in vivo.
Methods
We generated a novel fibroblast-specific p90RSK trangenic mouse strain and investigated the role of p90RSK in kidney fibrosis.
Results
We examined the expression of phospho-specific and total p90RSK during the course of chronic kidney injury in the classic unilateral ureter obstruction (UUO) model. It’s found that p90RSK is dramatically activated, as indicated by phosphorylation of p90RSK, in the obstructed kidneys as early as 3 days after UUO; and the activation continued increasing until 14 days after UUO when the mice were sacrificed. Whereas, there is little difference in the level of total p90RSK between the obstructed and control kidneys. Intriguingly, double immune staining analysis found that the activation of p90RSK in the interstitium is largely induced in the FSP-1-positive fibroblasts. We generated fibroblast-specific p90RSK transgenic mouse, p90RSK-Tg, and found that this mouse has normal phenotype as the littermate control. However, when UUO was induced in the p90RSK-Tg mice, it was found that p90RSK-Tg mice display significantly worse tubular damage, and dramatically increased deposition of extracellular matrix components such as collagen and fibronectin than that of their littermates. Western blot analysis also showed that p90RSK-Tg mice had decreased E-cadherin expression and de novo activation of alpha-SMA comparing to their littermates.
Conclusion
It is clear that fibroblast-specific p90RSK activation promotes kidney fibrosis, possibly, through the epithelial-to-mesenchymal transition mechanism.
Funding
- NIDDK Support