Biology subjects

Agranovich, B.

Publications and source records attributed to Agranovich, B..

4 recordsLinked to original sources

bioRxiv2026

Peripheral CB1R Blockade Suppresses AKI-to-CKD Maladaptive Repair

BackgroundAcute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), yet mechanisms governing this transition remain poorly understood. The endocannabinoid system (ECS), particularly cannabinoid-1 receptor (CB1R), regulates inflammation and metabolism in various organs, but its role in post-AKI maladaptive repair is less established. MethodsWe analyzed CB1R expression in kidney biopsies from pre- and post-transplant recipients and in murine AKI models (ischemia-reperfusion injury [IRI] and folic acid [FA]-induced AKI). Peripheral CB1R blockade was evaluated in FA-AKI model and in human primary kidney proximal tubule cells (hKPTCs). Spatial metabolomics, semi-targeted metabolomic profiling, and gene and protein expression characterized molecular mechanisms. ResultsCB1R expression was increased in kidneys undergoing maladaptive repair in both humans and mice, but remained unchanged during acute injury. In the FA-induced AKI model, the ECS showed stage-specific alterations, with temporal and spatial fluctuations in endocannabinoid levels and their enzymatic regulators. Peripheral CB1R blockade during the repair phase preserved kidney function, reduced injury, and maintained systemic glucose homeostasis. Metabolomic and molecular analyses revealed that CB1R blockade restored dysregulated arginine metabolism and reduced AKT/NF-{kappa}B-p65 pathway in post-AKI kidneys, linking CB1R activation to inflammatory signaling. In hKPTCs, 2-AG-induced activation of CB1R increased VCAM1 expression, a failed-repair marker, while its antagonism reduced TNF/2-AG-induced expression of pro-inflammatory adhesion molecules, chemokines, cytokines, and arginine metabolism enzymes. ConclusionsCB1R overactivation drives AKI-to-CKD progression by promoting inflammatory signaling and metabolic dysregulation. Peripheral CB1R blockade during the repair phase represents a novel therapeutic strategy to prevent maladaptive repair and CKD development after AKI. These findings establish CB1R as a phase-specific therapeutic target for post-AKI intervention. Translational StatementPeripheral CB1R antagonists offer a first-in-class therapeutic strategy to halt progression from acute kidney injury (AKI) to chronic kidney disease (CKD) by selectively targeting maladaptive tubular repair. By blocking CB1R signaling specifically in the kidney, these agents attenuate inflammation, metabolic dysregulation, and fibrogenic pathways that drive failed repair, while sparing central nervous system CB1R and thereby minimizing neuropsychiatric adverse effects. This phase-specific, peripherally restricted approach supports the development of peripheral CB1R antagonists as a viable translational therapy to improve long-term renal outcomes after AKI.

pharmacology and toxicology↗

bioRxiv2024

Limiting mitochondrial-derived ATP transfer to the cytosol enhances T-cell activation

T-cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generated T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, impeding NAD+ regeneration. Interestingly, Ant2-/- naive T cells exhibited enhanced activation, proliferation, and effector functions compared to wild-type controls. Metabolic profiling revealed that these cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Pharmacological inhibition of ANT in wild-type T cells recapitulated the Ant2-/- phenotype, and improved adoptive cell therapy of cancer. Our findings suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T-cell function. These results highlight the critical role of mitochondrial metabolism in regulating T-cell fate and underscore the therapeutic potential of targeting ANT for immune modulation.

immunology↗

bioRxiv2023

Fatty liver-mediated glycine restriction impairs glutathione synthesis and causes hypersensitization to acetaminophen

Non-alcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Understanding metabolic pathways involved can provide insights into disease progression. Untargeted metabolomics of livers from mice with early-stage steatosis indicated a decrease in methylated metabolites suggesting altered one carbon metabolism. The levels of glycine, a central component of one carbon metabolism, were lower in steatotic mice, in line with clinical evidence. Isotope tracing studies demonstrated that increased synthesis of serine from glycine is the underlying cause for glycine limitation in fatty livers. Consequently, the low glycine availability in steatotic livers impaired glutathione (GSH) synthesis under oxidative stress induced by acetaminophen (APAP), enhancing hepatic toxicity. Glycine supplementation mitigated acute liver damage and overall toxicity caused by APAP in fatty livers by supporting de novo GSH synthesis. Thus, early metabolic changes in NAFLD that lead to glycine depletion sensitize mice to xenobiotic toxicity even at a reversible stage of NAFLD.

biochemistry↗

bioRxiv2022

Sexual deprivation induces a CRF independent stress response and decreases resistance to stressors in Drosophila via a subpopulation of Neuropeptide F receptor-expressing neurons

Living in a changing environment composed of other behaving animals entails both opportunities and challenges to obtain resources and mating partners. Actions that promote survival and reproduction are reinforced by the brain reward systems, whereas coping with the challenges associated with obtaining these rewards are mediated by stress response pathways. The activation of the latter can impair health and shorten lifespan. Although similar responses to social opportunity and challenge exist across the animal kingdom, little is known about the mechanisms that process reward and stress under different social conditions. Here, we studied the interplay between deprivation of sexual reward and stress response in Drosophila melanogaster and discovered that repeated failures to obtain sexual reward induces a frustration-like state that is characterized by increased arousal, persistent sexual motivation, and impaired ability to cope with starvation and oxidative stressors. We show that this increased arousal and sensitivity to starvation is mediated by disinhibition of neurons that express receptors for the fly homologue of neuropeptide Y (neuropeptide F, NPF). We furthermore demonstrate the existence of an anatomical overlap between stress and reward systems in the fly brain in the form of neurons that co-express receptors for NPF (NPFR) and the corticotropin-releasing factor (CRF)-like homologue Diuretic hormone 44 (Dh44), and that deprivation of sexual reward leads to translocation of forkhead box-subgroup O (FoxO) to the cytoplasm in these neurons. Nevertheless, the activity of Dh44 neurons alone does not mediate sensitivity to starvation and aroused behavior following sexual deprivation, instead, these responses are mediated by disinhibition of ~12-16 NPFR-expressing neurons via a dynamin-independent synaptic signaling mechanism, suggesting the existence of a NPFR mediated stress pathway which is Dh44-independent. This paves the path for using simple model organisms to dissect mechanisms behind anticipation of reward, and more specifically, to determine what happens when expectations to obtain natural and drug rewards are not met.

animal behavior and cognition↗