Prostacyclin Mitigates Renal Fibrosis by Activating Fibroblast Prostaglandin I2 Receptor

Abstract

Background: Prostanoids have been demonstrated to be important modulators to maintain tissue homeostasis in response to physiological or pathophysiological stress. Prostacyclin (PGI2) is a member of prostanoids. While limited studies have shown that PGI2 is involved in the tissue injury/repairing process, its role in renal fibrosis and chronic kidney disease (CKD) progression requires further investigation. Methods: Prostacyclin synthase (Ptgis)-deficient mice, prostaglandin I2 receptor (Ptgir)-deficient mice, and an oral PGI2 analog and a selective PTGIR agonist were used to examine the role of PGI2 in renal fibrosis in mouse models. We also analyzed the single-cell RNA-Seq data to examine the PTGIR-expressing cells in the kidneys of CKD patients. Results: Increased PTGIS expression has been observed in fibrotic kidneys in both humans and mice. Deletion of PTGIS gene aggravated renal fibrosis and decline of renal function in murine models. A PGI2 analog or a PTGIR agonist that was administered after the acute injury ameliorated renal fibrosis. PTGIR, the PGI2 receptor, deficiency blunted the protective effect of the PGI2 analog. Fibroblasts and myofibroblasts were the major cell types expressing PTGIR in the kidneys of CKD patients. Deletion of PTGIR in collagen-producing fibroblastic cells aggravated renal fibrosis. The protective effect of PGI2 was associated with the inhibition of fibroblast activation via the PTGIR mediated signaling. Conclusions: PGI2 is an important component in the kidney injury/repairing process by preventing the over-activation of fibroblasts during the repairing process and protecting the kidney from fibrosis and decline of renal function. Our findings suggest that PGI2/PTGIR is a potential therapeutic target for CKD.