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The role of Regnase-2 knockout in renal proximal tubules

ABSTRACT: Regnase-2, an enzyme responsible for suppressing inflammation and producing toxins, including indole. This study used genetically engineered mice to explore the role of Regnase-2 (Reg-2) in kidneys. Using conditional knockout (Conditional KO) mouse models, renal proximal tubule–specific Inmt function was assessed. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined by RNA sequencing, histopathology, and various molecular assays. Those analyses were further complemented by immunofluorescence and electron microscopy to investigate cellular and structural alterations.Results: Inmt downregulation induced AKI associated with increased production of reactive oxygen species, and increased tubular apoptosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE316214 | GEO | 2026/03/28

REPOSITORIES: GEO

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The role of Inmt knockout in renal proximal tubules.

Project description:Indolethylamine N-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins, including indole. This study used genetically engineered mice to explore the role of Inmt in kidneys. Using conditional knockout (Conditional KO) mouse models, renal proximal tubule–specific Inmt function was assessed. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined by RNA sequencing, histopathology, and various molecular assays. Those analyses were further complemented by immunofluorescence and electron microscopy to investigate cellular and structural alterations.Results: Inmt downregulation induced AKI associated with increased production of reactive oxygen species, and increased tubular apoptosis.

2025-12-04 | GSE291123 | GEO

The role of Voclosporin administration and Inmt TG in renal proximal tubules.

Project description:Indolethylamine N-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins, including indole. We next investigated a strategy for preventing the significant decrease in Inmt expression in proximal tubules induced by high‑dose Voc administration and I/R. Accordingly, we used transgenic (Tg) mice with proximal tubule-specific Inmt overexpression and comparatively analyzed the changes with WT mice. Both WT and Tg mice were treated with high‑dose Voc, followed by I/R or sham operation for controls. Two experimental groups were campared using RNA-seq as follows: 1. I/R+WT+Voc (WT mice subjected to I/R and treated with high‑dose Voc)=WT+AKI, 2. I/R+Tg+Voc (Tg mice subjected to I/R and treated with high‑dose voclosporin)=TG+AKI. Results: Inmt-overexpressing mice treated with high-dose voclosporin exhibited absence of peroxisomal abnormalities and resistance to I/R injury.

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The transcriptional landscape associated with the deletion of Regnase-1 [ATAC-Seq]

Project description:Having identified the crucial role of IFN-γ in anti-tumor immunity of Reg-1ΔNK, we attempted to elucidate the mechanism underlying the regulation of Ifng in the context of Regnase-1 deletion. Despite the notable increase in Ifng mRNA expression in Reg-1ΔNK-NK cells, Ifng was not a direct substrate of Regnase-1. However, the production of the IFN-γ was further enhanced upon stimulation with IL-12/18. We proposed that modifications may have occurred in the transcriptional regulation of Ifng in Reg-1ΔNK-NK cells.

2024-05-30 | GSE237637 | GEO

The transcriptional landscape associated with the deletion of Regnase-1 [RNA-Seq]

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Effect of loss of Regnase-1 and Regnase-3 on the transcriptional profile in mouse Lin–Sca1+Kit+ (LSK) cells

Project description:Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that mRNA decay factors Regnase-1 (Zc3h12a) and Regnase-3 (Zc3h12c) are critical for induction of myeloid lineage priming, restricting lymphoid differentiation in HSPCs. Regnase-1- and Regnase-3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single cell-assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis revealed that Regnase-1 and Regnase-3 control the epigenetic landscape on myeloid-related gene loci in hematopoietic stem cells (HSCs) via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Regnase-1- and Regnase-3-mediated Nfkbiz mRNA degradation primed HSCs toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between post-transcriptional control and chromatin remodeling by the Regnase-1/Regnase-3-Nfkbiz axis governs lineage priming, instructing HSC lineage specification.

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Immune homeostasis and regulation of the Interferon pathway require myeloid-derived Regnase-3

Project description:The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-kB signaling. The roles of the other Regnase family-members remain largely unknown. Here, we analyze Regnase-3 deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased interferon signaling, which increased the proportion of immature B and innate immune cells and suppressed follicles and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Nevertheless, Regnase-3 expression is specifically high in macrophages and transcriptionally controlled by interferon signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade and regulate mRNAs, such Zc3h12a encoding Regnase-1, in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase and essential for immune homeostasis, but has diverged as a key regulator for the interferon pathway in macrophages.

2019-04-05 | GSE129325 | GEO

Genetically modifying the RNA-binding protein Regnase-1 reveals its critical role in Treg homeostasis and functions in vivo

Project description:Regnase-1 is a CCCH-type RNA-binding protein that degrades mRNA species via its ribonuclease activities to inhibit immune responses. But how and by what mechanisms Regnase-1 controls Foxp3+ Tregs in vivo remains poorly studied. Here we generated a conditional knock-in mouse in which a degradation-resistant Regnase-1 mutant (R111A) was selectively expressed in Foxp3+ Tregs as a transgene (Foxp3YFP-CreLSL-R111Afl/fl) to investigate the roles of Regnase-1 in Tregs. We found that all male Foxp3YFP-CreLSL-R111Afl/fl mice died of fatal autoimmune diseases by 4 weeks of age, which was accompanied by massive activation of T effector cells in vivo. We also found that the Foxp3+ Tregs in male Foxp3YFP-CreLSL-R111Afl/fl mice were depleted in the periphery, but not Tregs in the thymus. Further analyses revealed that the Foxp3+ Tregs expressing the Regnase-1 mutant R111A displayed an intrinsic survival defect and that transferring wild type Foxp3+ Tregs into the young male Foxp3YFP-CreLSL-R111Afl/fl mice could rescue the lethal autoimmune phenotype. Mechanistically, we demonstrated that the Regnase-1 readily degraded Bcl2l1 mRNA (encoding Bcl-xL) via binding to its stem loop structure, thus preventing Bcl-xL expression in Tregs. Consequently, Tregs expressing the Regnase-1 mutant R111A exhibited not only survival defects but also failure to respond to IL-2 in vivo, thus leading to their eventual demise. Together, our studies suggest that Regnase-1 can have a profound impact on Foxp3+ Tregs and that modulating Regnase-1 in Tregs may have important therapeutic implications.

2026-03-19 | GSE325328 | GEO

Crosstalk between the RNA-binding proteins Regnase-1 and -3 shapes mast cell survival and cytokine expression

Project description:Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) impacts immune cell responses, including mast cell functionality. Despite their importance in immune regulation, the functional role of most RBPs remains to be understood. By manipulating the expression of specific RBPs in murine mast cells, coupled with mass spectrometry and transcriptomic analyses, we found that the Regnase family of proteins acts as a potent regulator of mast cell physiology. Specifically, Regnase-1 is required to maintain basic cell proliferation and survival, while both Regnase-1 and -3 cooperatively regulate the expression of inflammatory transcripts upon activation, with Tnf being a primary target in both human and mouse cells. Further, Regnase-3 directly interacts with Regnase-1 in mast cells and is necessary to restrain Regnase-1 expression through the destabilization of its transcript. Overall, our study identifies protein interactors of endogenously expressed Regnase factors, characterizes the regulatory interplay between Regnase family members in mast cells, and establishes their role in the control of mast cell homeostasis and inflammatory responses.

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Regnase-1 overexpression/knockdown effect on primary mouse articular chondrocytes

Project description:Gene expression profiling of primary mouse articular chondrocyte infected with recombinant adenovirus expression mouse Regnase-1 or recombinant adenovirus expressing mouse small hairpin RNA of Regnase-1. In this study, we have attempted to explore the effects of Regnase-1 overexpression or knockdown on mouse transcriptome and have identified numerous genes which are involved in osteoarthritis pathogenesis.

2021-01-01 | GSE153179 | GEO

Crosstalk between Regnase-1 and -3 shapes mast cell survival and cytokine expression

Project description:Dysregulation of mast cell activation can lead to allergic and anaphylactic reactions. Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) is critical in controlling immune cell responses, including mast cell functionality. The Regnase family of RBPs plays a central role in regulating gene expression and controlling immune responses in both lymphoid and myeloid cells. However, what is the functional role of Regnase proteins in mast cells remains to be understood. Using different approaches of Regnase proteins depletion and deletion as well as overexpression by mRNA delivery, we found that Regnase-1 is a powerful negative regulator of mast cell proliferation, survival and ability to produce inflammatory cytokines. On the other hand, Regnase-3 was essential to modulate Regnase-1 expression in mast cells by direct targeting of the 3’-untranslated region of Regnase-1, leading to the destabilization of the Zc3h12a mRNA. Regnase-1 deletion had widespread effect on mast proliferation and survival even in the absence of stimulation and was at least in part linked to specific nuclear functions of Regnase-1 in modulating the ability of mast cells to withstand DNA damage. Overall, we describe the importance of Regnase proteins in modulating mast cell homeostatic and inflammatory responses and we describe the impact of Regnase-1 in the maintenance of genome stability.

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