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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 | GSE284133 | 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.
2025-07-02 | GSE284134 | GEO
Project description:Ptprz Signaling, Tubule and Macrophage-Mediated Renal Injury and Subsequent Chronic Kidney Disease
| PRJNA1197408 | ENA
Project description:Ptprz Signaling, Tubule and Macrophage-Mediated Renal Injury and Subsequent Chronic Kidney Disease [TECs]
| PRJNA1197423 | ENA
Project description:Ptprz Signaling, Tubule and Macrophage-Mediated Renal Injury and Subsequent Chronic Kidney Disease [macrophages]
| PRJNA1197422 | ENA
Project description:Incomplete repair after acute kidney injury can lead to development of chronic kidney disease. To define the mechanism of this response, we compared mice subjected to identical unilateral ischemia-reperfusion kidney injury with either contralateral nephrectomy (where tubule repair predominates) or contralateral kidney intact (where tubule atrophy predominates). By day 14, the kidneys undergoing atrophy had more macrophages with higher expression of chemokines, correlating with a second wave of proinflammatory neutrophil and T cell recruitment accompanied by increased expression of tubular injury genes and a decreased proportion of differentiated tubules. Depletion of neutrophils and T cells after day 5 reduced tubular cell loss and associated kidney atrophy. In kidney biopsies from patients with acute kidney injury, T cell and neutrophil numbers negatively correlated with recovery of estimated glomerular filtration rate. Together, our findings demonstrate that macrophage persistence after injury promotes a T cell- and neutrophil-mediated proinflammatory milieu and progressive tubule damage.
| S-EPMC9391331 | biostudies-literature
Project description:Incomplete repair after acute kidney injury (AKI) is associated with progressive loss of tubular cell function and development of chronic kidney disease (CKD). Here, we compared the kidney single-cell transcriptomes from the mice subjected to either unilateral ischemia-reperfusion kidney injury with contralateral nephrectomy (IRI/CL-NX, in which tubule repair predominates) or unilateral IRI with contralateral kidney intact (U-IRI, in which fibrosis and atrophy predominates) to investigate the mechanism(s) underlying transition to CKD following AKI.
2022-06-30 | GSE197626 | GEO
Project description:Excessive TGF-β signaling and mitochondrial dysfunction fuel chronic kidney disease (CKD) progression. However, inhibiting TGF-β failed to impede CKD in humans. The proximal tubule (PT), the most vulnerable renal segment, is packed with giant mitochondria and injured PT is pivotal in CKD progression. How TGF-β signaling affects PT mitochondria in CKD remained unknown. Here, we combine spatial transcriptomics and bulk RNAseq with biochemical analyses to depict the role of TGF-β signaling on PT mitochondrial homeostasis and tubulo-interstitial interactions in CKD. Male mice carrying specific deletion of Tgfbr2 in the PT have increased mitochondrial injury and exacerbated Th1 immune response in the aristolochic acid model of CKD, partly, through impaired complex I expression and mitochondrial quality control associated with a metabolic rewiring toward aerobic glycolysis in the PT cells. Injured S3T2 PT cells are identified as the main mediators of the maladaptive macrophage/dendritic cell activation in the absence of Tgfbr2. snRNAseq database analyses confirm decreased TGF-β receptors and a metabolic deregulation in the PT of CKD patients. This study describes the role of TGF-β signaling in PT mitochondrial homeostasis and inflammation in CKD, suggesting potential therapeutic targets that might be used to mitigate CKD progression.
| S-EPMC10239443 | biostudies-literature
Project description:Peroxisome proliferator-activated receptor-α (PPARα) activation attenuates cisplatin (CP)-mediated acute kidney injury by increasing fatty acid oxidation, but mechanisms leading to reduced renal triglyceride (TG) accumulation could also contribute. Here, we investigated the effects of PPARα and CP on expression and enzyme activity of kidney lipoprotein lipase (LPL) as well as on expression of angiopoietin protein-like 4 (Angptl4), glycosylphosphatidylinositol-anchored-HDL-binding protein (GPIHBP1), and lipase maturation factor 1 (Lmf1), which are recognized as important proteins that modulate LPL activity. CP caused a 40% reduction in epididymal white adipose tissue (WAT) mass, with a reduction of LPL expression and activity. CP also reduced kidney LPL expression and activity. Angptl4 mRNA levels were increased by ninefold in liver and kidney tissue and by twofold in adipose tissue of CP-treated mice. Western blots of two-dimensional gel electrophoresis identified increased expression of a neutral pI Angptl4 protein in kidney tissue of CP-treated mice. Immunolocalization studies showed reduced staining of LPL and increased staining of Angptl4 primarily in proximal tubules of CP-treated mice. CP also increased TG accumulation in kidney tissue, which was ameliorated by PPARα ligand. In summary, a PPARα ligand ameliorates CP-mediated nephrotoxicity by increasing LPL activity via increased expression of GPHBP1 and Lmf1 and by reducing expression of Angptl4 protein in the proximal tubule.
| S-EPMC3433869 | biostudies-literature
Project description:To investigate how TGF-b affects proximal tubule cell metabolism and response to injury, we generated conditional immortalized mouse PT cells and deleted the TGF-beta Receptor II in vitro using adeno-cre We then performed gene expression profiling analysis using data obtained from RNA-seq of WT cells (PT cre-) and KO cells (PTcrex2) treated or not with H2O2 in serum free media (4 conditions in total)
2023-04-18 | GSE225545 | GEO