Abstract
Purpose :
Retinopathy of prematurity (ROP) is the leading cause of blindness in premature infants, and available therapies are often associated with severe side effects. Our previous studies using RNA-sequencing have demonstrated disruption of sterol and bile acids (BA) metabolism in an experimental model of ROP (oxygen-induced retinopathy; OIR). Our preliminary data suggested the presence of BA receptors in the retina discloses the existence of BA-related signaling mechanisms and explains their effects in OIR mice. We hypothesized that alterations in retinal farnesoid X receptor (FXR; a nuclear BA receptor) signaling play a key role in ROP pathogenesis and the pharmacological modulation of these pathways represents a new therapeutic tool in limiting ROP pathology.
Methods :
Changes in mRNA expression of various BA receptors in the developing mice retina were studied using qPCR. mRNA and protein expression of FXR receptor in postnatal and OIR mice retinas were studied using qPCR and western blotting assays. In addition, seven days old (P7) wild-type (WT) and FXR-/- mice were subjected to the OIR procedure, retinas were collected at P17, and retinal flat mounts were stained with isolectin B4 to study vascular distribution in these mice retinas. Lastly, WT mice were treated with an FXR agonist, obeticholic acid (OCA; 50 mg/kg/day from P7-P17), and the vascular pathology in OIR mice were analyzed at P17.
Results :
FXR was the most highly expressed nuclear BA receptor. While the FXR expression remained consistent throughout the retinal development and adult retina, its expression significantly decreased in OIR mice compared to RA. Further results obtained using FXR-/- mice indicated that the absence of FXR does not affect normal vasculature development; it plays a significant role in OIR pathology. Lastly, treatment with OCA improved the vascular pathology in OIR mice, as evidenced by the decreased number of neovascular tufts and size of the avascular areas compared to untreated OIR mice. Further unbiased vascular network analysis revealed that OCA-treated mice had increased vessel length, junction density, and fewer endpoints compared to untreated OIR mice retina vasculature.
Conclusions :
Our data suggest that endogenous retinal BA synthesis and subsequent FXR signaling are compromised in OIR mice, OIR pathology is exacerbated in FXR null mice and is ameliorated by an FXR-specific agonist, OCA.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.