Prostacyclin Mitigates Renal Fibrosis by Activating Fibroblast Prostaglandin I2 Receptor

Abstract

Significance Statement Renal fibrosis is a common pathologic process of progressive CKD. We have provided strong evidence that PGI2 is an important component in the kidney injury/repairing process by reducing fibrosis and protecting renal function from declining. In our study, administration of a PGI2 analog or selective PTGIR agonist after the acute injury ameliorated renal fibrosis. Our findings provide new insights into the role of PGI2 in kidney biology and suggest that targeting PGI2/PTGIR may be a potential therapeutic strategy for CKD. Background Prostanoids have been demonstrated to be important modulators to maintain tissue homeostasis in response to physiologic or pathophysiologic 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 CKD progression requires further investigation. Methods Prostacyclin synthase (Ptgis)-deficient mice, prostaglandin I2 receptor (Ptgir)-deficient mice, and an oral PGI2 analog and 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 patients with CKD. Results Increased PTGIS expression has been observed in fibrotic kidneys in both humans and mice. Deletion of the PTGIS gene aggravated renal fibrosis and decline of renal function in murine models. A PGI2 analog or 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 patients with CKD. Deletion of PTGIR in collagen-producing fibroblastic cells aggravated renal fibrosis. The protective effect of PGI2 was associated with the inhibition of fibroblast activation through PTGIR-mediated signaling. Conclusions PGI2 is an important component in the kidney injury/repairing process by preventing the overactivation 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.