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Kidney Week

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Abstract: TH-PO483

The Protective Effect of Prostacyclin in Renal Fibrosis

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Li, Jing, Hushan Hospital, Fudan University, Shanghai, China
  • Hao, Chuan-Ming, Hushan Hospital, Fudan University, Shanghai, China
Background

Progressive decline of renal function is a hallmark of CKD, the mechanism of which is incompletely understood. Inadequate repairing process to injury has been reported to play an important role. Mounting evidence suggests that prostaglandins are important in serving as a “buffer”in response to physiological changes or pathophysiologic insults to tissues including the kidney. Importantly, under certain conditions such as aging and hypertension, prostacyclin (PGI2), an active production of COX/PGI2 Synthase (PGIS), is reduced. The present study provides data showing that PGI2 plays an important role in response to renal injury to maintain adequate injury and repairing process. Low levels of PGI2 are associated with enhanced renal fibrosis.

Methods

Mice with global PGIS gene deletion were obtained by crossing the floxed PGIS mice with the EIIA-Cre mice. The endothelial-specific PGIS-deficient mice were generated by mating the floxed PGIS mice with the TEK-CRE (Tie2-CRE) mice. Unilateral ureteral obstruction (UUO)was used as a renal fibrosis model. At days 10 after UUO, the mice were sacrificed, and the kidneys were collected.

Results

Immunohistochemistry showed that PGIS is primarily expressed in endothelial cells and vascular smooth muscle cells. The expression of PGIS was markedly induced following AKI and fibrotic kidney. Enhanced PGIS expression is associated with increased PGI2 level.
Losing one allele of PGIS ( PGIS+/-) significantly aggravated UUO -induced renal fibrosis, showing increased fibronectin, collagen I and α-SMA, and more extracellular matrix deposition in the section at 10 days after UUO comparing to their wild type littermates. Kidney thromboxane synthase expression is not significantly different between PGIS+/- mice and wild type littermates after UUO. Loss of one allele of PGIS did not change blood pressure.
To examine the role of specific cells that express PGIS in renal fibrosis, we specifically deleted PGIS in endothelial cells. Endothelial-specific PGIS-deficient mice had normal blood pressure and renal function. Endothelial PGIS gene deletion also significantly aggravated UUO -induced renal fibrosis. Furthermore, the level of phosphorylated PKA substrates in the kidney of deficient mice was significantly reduced.

Conclusion

PGIS/PGI2 plays an important role in protecting the kidney from fibrosis. Lack of PGIS enhances kidney damage. PGIS/PGI2 is a potential target for CKD.

Funding

  • Government Support - Non-U.S.