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Kidney Week

Abstract: FR-PO350

Endothelial Sirtuin 1 Deficiency Is a Super-Inducer of Syndecan 4 (Synd4): Role of Its Ectodomain in Renal Fibrosis

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Lipphardt, Mark, New York Medical College, Valhalla, United States
  • Song, Jong Wook, Yonsei University College of Medicine, Millwood, New York, United States
  • Ratliff, Brian B., New York Medical College, Valhalla, New York, United States
  • Dihazi, Hassan, University Medical Centre Goettingen, Goettingen, Germany
  • Mueller, Gerhard A., Georg-August University, Gottingen, Germany
  • Goligorsky, Michael S., New York Medical College, Valhalla, New York, United States
Background

Syndecans comprise a family of membrane-spanning, glycocalyx-forming proteoglycans with glycosaminoglycans covalently bound to their ectodomain. There is evidence that Synd4 is required for integrin function and wound healing, but mice with the deletion of Synd4 appeared to be protected from renal fibrosis. Synd4 expression is regulated by NF-kB activity while degradation of the latter requires deacetylation by Sirtuin 1 (Sirt1).

Methods

To elucidate the role of Synd4 in fibrosis, we compared wild type and fibrosis-prone endothelial Sirt1-deleted Sirt1endo-/- mice serving as a model of global endothelial dysfunction.

Results

Synd4 transcripts were dramatically increased in Sirt1endo-/- kidneys. UUO further induced it in control but especially in Sirt1endo-/- mouse kidneys. Synd4 ectodomain expression was significantly enhanced after UUO compared to contralateral kidneys, whereas there were no differences in expression of the intracellular domain. We next performed mass-spectrometry analysis of the secretome of renal microvascular endothelial cells (RMVEC) which revealed that Synd4 was highly enriched in TGFβ1- stimulated cells obtained from Sirt1endo-/- mice; notably all detectable peptides were confined to the ectodomain of Synd4. Furthermore, hyperplasia of myofibroblasts accompanied by microvascular rarefaction and overexpression of Synd4 were detected in Sirt1endo-/- mouse kidneys. The ectodomain of Synd4 acted as a chemoattractant for monocytes with higher levels of macrophages and higher expression level of Synd4 detected in the extracellular matrix of Sirt1endo-/- mice. In vitro, ectodomain application resulted in generation of myofibroblasts from cultured renal fibroblasts, while in vivo, subcapsular injection of ectodomain induced interstitial fibrosis.

Conclusion

Based on our experimental results and the existing body of published work, we propose that it is the Synd4 ectodomain rather than Synd4 per se that is partially responsible for fibrosis in UUO and, especially, when it is combined with endothelial dysfunction.