Biology subjects

Jadeja, R. N.

Publications and source records attributed to Jadeja, R. N..

4 recordsLinked to original sources

bioRxiv2026

Loss of Farnesoid X Receptor Signaling Promotes Choroidal Neovascularization in Mice

Choroidal neovascularization (CNV) is a defining feature of neovascular age-related macular degeneration (nAMD). Although anti-vascular endothelial growth factor (VEGF) therapies suppress neovascular activity, incomplete responses, recurrent leakage, and subretinal fibrosis remain important clinical challenges. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor with anti-inflammatory, anti-fibrotic, and anti-angiogenic functions in other tissues, but its role in CNV is unknown. Analysis of publicly available human transcriptomic data (GSE135092) showed FXR expression in the retinal pigment epithelium (RPE)/choroid and significant downregulation in AMD-affected macular RPE/choroid. To define the role of FXR in CNV, laser photocoagulation was performed in wild-type (WT) and FXR-deficient (FXR-KO) mice, with disease progression assessed by in vivo imaging, histology, ex vivo choroidal sprouting, and endothelial cell assays. FXR expression in the RPE/choroid was reduced 14 days after laser injury. Compared with WT mice, FXR-KO mice developed larger CNV lesions, more extensive hyperfluorescence on fluorescein angiography, and increased lesion area during disease progression. FXR deficiency also impaired resolution of fibrotic remodeling. In WT mice, alpha-SMA peaked at day 14 and declined by day 21, whereas collagen I remained low throughout; in FXR-KO mice, both collagen I and alpha-SMA were significantly elevated relative to WT and remained significantly higher than WT at day 21. Consistent with these findings, FXR-deficient choroidal explants exhibited increased vascular sprouting, and FXR-KO endothelial cells formed more extensive capillary-like networks. Together, these findings identify FXR as an endogenous regulator of pathological angiogenesis, vascular leakage, mesenchymal activation, and fibrotic remodeling during CNV and provide a rationale for investigating FXR-directed strategies for nAMD.

biochemistry↗

bioRxiv2025

CYP46A1 Activation Improves Retinal Neovascularization in a Mouse Model of Retinopathy of Prematurity

Previous studies have shown the metabolic and regulatory significance of CYP46A1 in the adult retina; however, its role in the developing retina is unknown. Here, we evaluate CYP46A1 expression and the impact of its activation in the developing mouse retina under normal and pathological conditions. Seven-day-old (P7) C57BL/6J mice maintained in room air (controls) or subjected to oxygen-induced retinopathy (OIR) were treated with/without 20 mg/kg efavirenz (EFV), a CYP46A1 activator administered intraperitoneally from P7 to P17. Retinal cross sections and flat mounts were prepared to study retinal vasculature morphology, Muller and microglia activation, and ganglion cell viability. EFV treatment significantly reduced pathological neovascularization and the size of avascular and hypoxic areas in OIR mice retinas. EFV treatment additionally limited reactive gliosis and microglia activation and improved retinal ganglion cell survival in OIR mice. The current study demonstrates the developmental regulation of CYP46A1 and the dysregulated expression and levels of the downstream metabolite 24-Hydroxycholesterol (24HC) in OIR mice. The study further suggests that pharmacological CYP46A1 activation may improve key pathological features associated with pathological neovascularization in OIR mice.

biochemistry↗

bioRxiv2024

Protective Effects of Butyrate on Retinal Neovascularization in Preclinical Retinopathy of Prematurity Models

Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide, necessitating new therapeutic strategies. Current interventions targeting advanced disease stages often fail to prevent long-term visual impairment. This study investigates the potential of sodium butyrate (NaB), an orally administered short-chain fatty acid, in preclinical models of ROP. Using the oxygen-induced retinopathy (OIR) mouse model, we demonstrate that daily oral NaB supplementation significantly protects against pathological angiogenesis, impacting not only vascular but also neuronal and microglial pathology in the inner retina. Notably, NaB shows efficacy in early-phase ROP intervention, as evidenced by studies in postnatal day 9 (P9) OIR mice and a novel hyperglycemia-associated retinopathy (HAR) model that mimics the hyperglycemic conditions of many premature infants. These findings highlight NaB as a promising alternative or adjunct therapy to current anti-VEGF treatments, offering protection across multiple retinal cell types and stages of ROP development. The study underscores the need for further research to elucidate the specific mechanisms of NaBs action, paving the way for its potential clinical application in ROP management. This research marks the first exploration of butyrate as a preventative and therapeutic agent for ROP, setting the stage for additional preclinical evaluations and optimization.

pharmacology and toxicology↗

bioRxiv2021

Hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) expression and signaling promotes the maintenance of an immunoinhibitory retinal environment

BackgroundExcessive oxidative stress and related chronic, sub-clinical inflammation is linked causally to the development and progression of degenerative diseases of the retina including diabetic retinopathy, age-related macular degeneration and glaucoma, leading causes of blindness worldwide. The above responses may be related directly to dysregulated retinal immunity and are potentiated by the combined actions of native retinal cells (e.g., retinal pigment epithelial (RPE) and microglial cells) and immune cells infiltrating from the periphery. Maintaining tight regulation of these cells such that effective control of pathogens is accomplished yet uncontrolled inflammation and consequent tissue damage is prevented is extremely important. However, the molecular mechanisms that control this delicate balance are poorly understood. We hypothesize that the hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) may play an important role. HCAR2/GPR109A has been shown to regulate immune cell responses that potentiate anti-inflammatory signaling upon its activation in various tissues as evidenced principally by suppressed pro-inflammatory cytokine secretion in various experimental model systems. We have demonstrated HCAR2/GPR109A expression in RPE, microglia and endothelial cells and, our in vitro studies support that the receptor elicits anti-inflammatory signaling in these cell types. However, the functional relevance of HCAR2/GPR109A expression and its activation in the retina of the living animal has not been demonstrated definitively. This is the purpose of the present study. MethodsRetinal function was evaluated temporally in wildtype (Hcar2/Gpr109a +/+, WT) and knockout (Hcar2/Gpr109 -/-, KO) mice via electroretinography (ERG). Fundoscopic imaging, spectral domain-optical coherence tomography (OCT), fluorescein angiography and post-mortem histological analyses were additionally performed to evaluate retinal health. Gene microarray, RT-qPCR studies, ingenuity analyses and proteome pathway mapping were performed to evaluate potential key differences in the molecular signatures of WT and KO mouse retinas. Leukostasis and flow cytometric assays were performed to demonstrate the in vivo impact of HCAR2/GPR109A expression and its therapeutic activation on pro-inflammatory immune cell trafficking in retina. ResultsLongitudinal studies revealed progressive anomalies in retinal morphology and function in HCAR2/GPR109A knockout mice that impacted the entire retina. Gene expression and protein interactome analyses revealed differences in gene and protein expression consistent with the increased immune reactivity and infiltration of bone-marrow derived immune cells detected in KO mouse retinas. Studies conducted in an acute model of retinal (endotoxin-induced) inflammation revealed that targeting the receptor via intraperitoneal administration of agonist, beta-hydroxybutyrate, limits immune cell activation, infiltration and related inflammation in WT retinas. ConclusionsThe present studies demonstrate a central role for HCAR2/GPR109A in regulating the complex interplay between resident retinal cells and peripheral immune cells and, the potential therapeutic utility that targeting the receptor holds with respect to preventing and treating inflammatory retinal diseases. HighlightsOxidative stress and inflammation are major causative factors in degenerative retinal diseases stemming from numerous causes (e.g., aging, diabetes, sickle cell). Thus, identifying new targets and developing strategies to counter these factors to prevent and treat retinal degeneration is important. The present in vivo study demonstrates convincingly the principal role of the hydroxycarboxylic acid receptor 2 (HCAR2/GPR109A) as a major regulator of retinal immune responses under normal conditions and therefore, as a target with extremely high potential for therapeutic modulation of these responses in retinal disease.

biochemistry↗