The m5C orchestrator NSUN7 drives SPARC/HMGB1 axis–mediated inflammation to exacerbate kidney injury [MeRIP-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE292304 | GEO | 2026/03/15
REPOSITORIES: GEO
Dataset's files
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Project description:Growing evidence indicates that kidney inflammation is a major contributor to the pathogenesis of various renal diseases, including acute kidney injury (AKI). Although RNA modifications have been implicated in regulating kidney inflammation, their precise roles remain largely unknown. Here, we show that kidney inflammation and injury were associated with elevated RNA 5-methylcytosine (m5C) modifications, primarily driven by the m5C “writer” NOP2/Sun RNA methyltransferase family member 7 (NSUN7). Both global and kidney-specific deletion of Nsun7 in mice reduced m5C abundance, attenuated inflammatory responses, and decreased macrophage infiltration, underscoring its proinflammatory role in the kidney. Mechanistically, we identified secreted protein acidic and cysteine-rich (SPARC) as a major downstream effector of NSUN7. SPARC upregulation amplified inflammatory responses in renal tubular epithelial cells by interacting with high mobility group box 1 and further promoted proinflammatory macrophage infiltration via tubular-macrophage crosstalk. Notably, therapeutic silencing of Nsun7 using a kidney-specific DNA tetrahedral molecular carrier developed for this study effectively alleviated inflammation and improved renal outcomes in AKI models. Collectively, our findings identify NSUN7 as a key driver of renal inflammation via SPARC regulation and underscore its potential as a therapeutic target in inflammatory kidney diseases.
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Project description:Background: Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to acute kidney injury (AKI). Ischemia/reperfusion injury (I/R) triggers tubular epithelial cells to express IL-34, a macrophage growth factor, that promotes AKI and subsequent CKD. IL-34 engages the cognate receptor, c-FMS, expressed by macrophages, and the recently discovered Protein-Tyrosine Phosphatase Z (Ptprz). Ptprz, binds to multiple ligands other than IL-34 that progressively increase their expression in kidneys after I/R. Methods: We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated AKI and subsequent CKD, by comparing Ptprz knockout (KO) with wild-type (WT) mice after I/R. Results: Ptprz was expressed by leukocytes and in tubular epithelial cells after I/R in mice. Using Ptprz KO mice we determined that during AKI and CKD renal pathology, and loss of renal function were ameliorated. Ptprz-dependent mechanisms mediated: (i) tubular epithelial cell expression of chemokines that fostered macrophage and T cell rich renal inflammation, and (ii) tubule injury and apoptosis, that resulted in the loss of tubules and interstitial fibrosis during CKD. As macrophages release mediators that induce tubular epithelial cell apoptosis, thus Ptprz-dependent mechanisms promote tubule damage. These findings are translational, as after I/R in human kidney transplants, PTPRZ and PTPRZ ligands were upregulated and expressed by the same cell populations as in mice. Moreover, PTPRZ levels in sera were elevated in kidney transplant patients. Conclusion: Intra-renal Ptprz-dependent macrophage and tubular epithelial cell mediated mechanisms promote AKI and subsequent CKD.
2025-07-02 | GSE284134 | GEO
Project description:Background: Macrophages and tubular epithelial cell interactions are integral in kidney ischemia-incited interstitial inflammation leading to acute kidney injury (AKI). Ischemia/reperfusion injury (I/R) triggers tubular epithelial cells to express IL-34, a macrophage growth factor, that promotes AKI and subsequent CKD. IL-34 engages the cognate receptor, c-FMS, expressed by macrophages, and the recently discovered Protein-Tyrosine Phosphatase Z (Ptprz). Ptprz, binds to multiple ligands other than IL-34 that progressively increase their expression in kidneys after I/R. Methods: We tested the hypothesis that signaling through Ptprz promotes macrophage-mediated AKI and subsequent CKD, by comparing Ptprz knockout (KO) with wild-type (WT) mice after I/R. Results: Ptprz was expressed by leukocytes and in tubular epithelial cells after I/R in mice. Using Ptprz KO mice we determined that during AKI and CKD renal pathology, and loss of renal function were ameliorated. Ptprz-dependent mechanisms mediated: (i) tubular epithelial cell expression of chemokines that fostered macrophage and T cell rich renal inflammation, and (ii) tubule injury and apoptosis, that resulted in the loss of tubules and interstitial fibrosis during CKD. As macrophages release mediators that induce tubular epithelial cell apoptosis, thus Ptprz-dependent mechanisms promote tubule damage. These findings are translational, as after I/R in human kidney transplants, PTPRZ and PTPRZ ligands were upregulated and expressed by the same cell populations as in mice. Moreover, PTPRZ levels in sera were elevated in kidney transplant patients. Conclusion: Intra-renal Ptprz-dependent macrophage and tubular epithelial cell mediated mechanisms promote AKI and subsequent CKD.
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Project description:Acute kidney injury (AKI) is a global public health concern associated with high morbidity and mortality, and currently no therapeutic interventions reliably limit injury or speed recovery after AKI. Therefore, strategies to augment endogenous repair processes and retard associated profibrotic responses are urgently required. Among them, macrophages are attractive therapeutic targets for AKI because of their critical roles in tissue homeostasis and inflammation. Despite the differentiation of macrophages into morphologically and functionally distinct phenotypes M1/M2 and their clearance of dead cells (efferocytosis) have been increasingly linked to renal inflammation and repair in AKI, the underlying mechanisms of macrophage phenotype switching and efferocytosis during AKI are largely unclear. Here, we found that JAML (junctional adhesion molecule-like protein) deficiency protected against renal AKI. By generation of bone marrow chimeric mice and tubular-specific JAML conditional knockout mice, we demonstrated macrophage JAML primarily contributed to AKI. Mechanistically, JAML mediated macrophage phenotype polarization and efferocytosis, at least in part, through a C-type lectin receptor Mincle-dependent mechanism. In addition, we also found that JAML could induce endogenous Mincle ligand such as SAP130 release from dead or dying renal tubular epithelial cells and subsequent Mincle activation in macrophages, thereby also slightly contributing to AKI. Importantly, we observed a higher expression of JAML in the kidney from subjects with AKI and the level of JAML was correlated with serum creatinine. Collectively, our studies for the first time explore new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacologic targeting of JAML-Mincle mediated signaling pathways may provide a novel therapeutic strategy for patients with AKI.
2021-12-23 | GSE192532 | GEO
Project description:Background: Pyroptosis plays a critical role in eliminating pathogens and facilitating tissue repair; however, sustained pyroptosis-driven inflammation accelerates kidney injury and disease progression. Thus, elucidating the mechanisms governing pyroptosis is essential for developing effective therapies for inflammatory kidney diseases such as acute kidney injury (AKI), which currently lacks specific treatment options. Methods: Changes in tubular epithelial cells following drug-induced AKI were assessed using single-cell RNA sequencing, immunohistochemistry, and immunofluorescence. Mechanistic insights were obtained through RNA sequencing, genomic manipulation, transcriptomic profiling, luciferase reporter assays, co-immunoprecipitation, and Western blotting. Tubular epithelial cell fate was further evaluated using transgenic mouse models and pharmacological interventions. Results: We identified activating transcription factor 4 (ATF4) as a key regulator of inflammation in drug-induced AKI. As the master regulator of the integrated stress response, ATF4 was markedly upregulated in renal tubules and positively correlated with kidney dysfunction in both human and murine AKI models. The specific deletion of ATF4 in tubular epithelial cells significantly ameliorated kidney dysfunction, inflammation, and mitochondrial apoptosis, whereas ATF4 activation exacerbated these pathological features. Mechanistically, ATF4 suppression inhibited STAT1 phosphorylation and disrupted its interaction with GBP2, thereby attenuating NLRP3 inflammasome activation, preventing tubular epithelial cells' pyroptosis, and improving kidney function. Notably, inhibition of ATF4—either pharmacologically using our prioritized integrated stress response antagonist ERMT1 or through engineered nanobiologics-mediated silencing of tubular epithelial cells—significantly reduced renal inflammation and injury. Conclusions: ATF4 promoted pyroptosis in drug-induced AKI through STAT1–GBP2 signaling.
2025-12-11 | GSE313125 | GEO
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