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Kidney Week

Abstract: SU-OR15

Protective Effect of Prostacyclin in Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Li, Jing, Division of Nephrology, Huashan Hospital Fudan University, Shanghai, China
  • Hao, Chuan-Ming, Division of Nephrology, Huashan Hospital Fudan University, Shanghai, China
Background

Inadequate repairing process to injury has been reported to play an important role in renal fibrosis. 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 low levels of PGI2 are associated with enhanced renal fibrosis.

Methods

Unilateral ureteral obstruction (UUO) was used as a renal fibrosis model. At days 10 after UUO, the mice were sacrificed. Ischemia-reperfusion (I/R) model was induced by clamping the left renal pedicle for 35 minutes on D0. After 4 weeks, the right kidney was removed. The mice were treated with beraprost sodium (300μg/kg bodyweight per day by twice daily gavage) or vehicle from D32 to D55, and were sacrificed on D56.

Results

The PGIS heterozygous (PGIS+/-) mice had normal body weight, blood pressure and blood urea nitrogen (BUN) level. Losing one allele of PGIS significantly attenuated the increase of PGIS expression after UUO and aggravated UUO -induced renal fibrosis, showing increased levels of fibronectin, collagen I and α-SMA compared with wild-type littermates. Masson trichrome staining shows more extracellular matrix accumulation in the kidney of PGIS+/- mice after UUO. Endothelial PGIS gene deletion also significantly attenuated the increase of PGIS expression after UUO and aggravated UUO-induced renal fibrosis.
I/R model was performed on wild-type mice. Treatment with beraprost sodium (BPS), a analog of PGI2, inhibited the expression of fibronectin, collagen I and α-SMA in the kidney and ameliorated extracellular matrix deposition in the histology study.
Furthermore, the level of phosphorylated PKA substrates in the ureteral obstructed kidney of deficient mice was significantly reduced, suggesting the role of IP receptor. IP agonist treatment reduced the expression of fibronectin, collagen I and α-SMA in rat renal fibroblasts (NRK-49F), which were induced by TGF-β.

Conclusion

PGIS/PGI2 plays an important role in protecting the kidney from fibrosis. Lack of PGIS enhances renal fibrosis, and supplementation with PGI2 analog ameliorates renal fibrosis. PGIS/PGI2 is a potential target for CKD.