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Abstract: FR-PO142

Regulating Hyaluronan Deposition Attenuates Tubulointerstitial Fibrosis in Ureteral Obstruction

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Wang, Xinyi, Baylor College of Medicine, Houston , Texas, United States
  • Balaji, Swathi, Baylor College of Medicine, Houston, Texas, United States
  • Steen, Emily, Baylor College of Medicine, Houston, Texas, United States
  • Li, Hui, Baylor College of Medicine, Houston, Texas, United States
  • Blum, Alexander, Baylor College of Medicine, Houston, Texas, United States
  • Austin, Paul, Texas Children's Hospital, Houston, Texas, United States
  • Bollyky, Paul L., Stanford University, Stanford, California, United States
  • Wight, Thomas N., Benaroya Research Institute, Seattle, Washington, United States
  • Cheng, Jizhong, Baylor College of Medicine, Houston, Texas, United States
  • Keswani, Sundeep G., Baylor College of Medicine, Houston, Texas, United States

Group or Team Name

  • Laboratory for Regenerative Tissue Repair
Background

Renal fibrosis is an end-stage outcome of chronic kidney disease(CKD) without foreseeable cure. However, we recently found that interleukin-10 (IL-10) can abrogate dermal fibrosis by regulating hyaluronan(HA), an abundant glycosaminoglycan in the extracellular matrix (ECM). Here, we hypothesize that promoting the expression of the high molecular weight(MW) HA form attenuates renal fibrosis by regulating ECM remodeling and reducing inflammation.

Methods

in vivo: we used the UUO model in the presence or absence of IL-10 to assess the HA role. UUO/sham kidneys were collected at d3,7,14&21 for RNA, ELISA, and/or IHC analyses. HA synthases(HAS1-3) and hyaluronidases(HYAL1-2) enzyme levels were determined by qPCR and immunoblotting (IB), while HA MW was confirmed by gel electrophoresis. To test loss of function effects, we fed mice with 4-methylumbelliferone(4-MU,5%), a HA synthesis inhibitor, and evaluated the outcomes.in vitro: renal fibroblasts(FB) were isolated from C57BL/6J mice to measure total HA by pericellular matrix assays. α-SMA, HAS1, 2 and p-STAT3 expression were also assessed by IB at 48h. Mean ±SD; p-values by ANOVA.

Results

in vivo: HAS1 & HAS2 expression was upregulated in normal and 4MU-fed UUO mice compared to control mice from d3 onwards. ELISA showed that total HA levels steadily increased from d3-14 for UUO mice, and up to d21 for IL-10-treated UUO mice. In normal diet mice, lenti-IL-10 resulted in decreased kidney fibrosis and preserved tubular integrity in comparison to controls. IL-10-treated 4-MU diet mice did not attenuated fibrosis. HA gel electrophoresis showed that unlike control/sham kidneys, d3&7 UUO kidneys had a previously unreported 1.5x106D HA form. in vitro: A 1.88-fold increase in HA-rich matrix formation was shown with 24h of IL-10 stimulation, and the effect was abrogated by HYAL. Significant increased HAS2, α-SMA, & p-STAT3 in the IL-10-treated FBs after 48h. p<0.05

Conclusion

Our study provides the first evidence that injured mouse kidney expresses increased levels of an ultra-high MW HA variant not found in normal kidneys. This suggests that HA is critical for kidney function, homeostasis, and architectural integrity. Understanding the mechanisms behind HA-mediated in renal fibrosis could lead the design and application of innovative therapeutics.

Funding

  • Other NIH Support