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Project description:Background: Acute kidney injury (AKI) is associated with damage to the nephrons and tubular epithelial cells (TECs), which can lead to chronic kidney disease and end-stage renal disease. Identifying new biomarkers before kidney dysfunction will offer crucial insight into preventive and therapeutic options for the treatment of AKI. Early growth response 1 (EGR1) has been found to be a pioneer transcription factor that can sequentially turn on/off key downstream genes to regulate whole-body regeneration processes in the leopard worm. Whether EGR1 modulates renal regeneration processes in AKI remains to be elucidated. Methods: AKI models of ischemia-reperfusion injury (IRI) and folic acid (FA) were developed to investigate the roles of EGR1 in kidney injury and regeneration. To further determine the function of EGR1, Egr1-/- mice were applied. Furthermore, RNA sequencing of renal TECs, Chromatin Immunoprecipitation (ChIP) assay, and Dual-luciferase reporter assay were carried out to investigate whether EGR1 affects the expression of SOX9. Results: EGR1 is highly expressed in the kidney after AKI both in humans and mice through analysis of the Gene Expression Omnibus (GEO) database. Furthermore, we verified that EGR1 rapidly up-regulates in the very early stage of IRI and nephrotoxic models of AKI, and validation studies confirmed the essential roles of EGR1 in renal tubular cell regeneration. Further experiments affirmed that genetic inhibition of Egr1 aggravates the severity of AKI in mouse models. Furthermore, our results revealed that EGR1 could increase SOX9 expression in renal TECs by directly binding to the promoter of the Sox9 gene, thus promoting SOX9+ cell proliferation by activating the Wnt/β-catenin pathway. Conclusions: Together, our results demonstrated that rapid and transient induction of EGR1 plays a renoprotective role in AKI, which highlights the prospects of using EGR1 as a potential therapeutic target for the treatment of AKI.
| S-EPMC9330523 | biostudies-literature
Project description:Transient upregulation of EGR1 signaling enhances kidney repair by activating SOX9+ renal tubular cells
| PRJNA731663 | ENA
Project description:Macroautophagy/autophagy contributes to maladaptive kidney repair by inducing pro-fibrotic factors such as FGF2 (fibroblast growth factor 2), but the underlying mechanism remains elusive. Here, we show that EGR1 (early growth response 1) was induced in injured proximal tubules after ischemic acute kidney injury (AKI) and this induction was suppressed by autophagy deficiency in inducible, renal tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7 KO) mice. In cultured proximal tubular cells, TGFB1 (transforming growth factor beta 1) induced EGR1 and this induction was also autophagy dependent. Egr1 knockdown in tubular cells reduced FGF2 expression during TGFB1 treatment, leading to less FGF2 secretion and decreased paracrine effects on fibroblasts. ChIP assay detected an increased binding of EGR1 to the Fgf2 gene promoter in TGFB1-treated tubular cells. Both Fgf2 and Egr1 transcription was inhibited by FGF2 neutralizing antibody, suggesting a positive feedback for EGR1-mediated FGF2 autoregulation. This feedback was confirmed using fgf2-deficient tubular cells and fgf2-deficient mice. Upstream of EGR1, autophagy deficiency in mice suppressed MAPK/ERK (mitogen-activated protein kinase) activation in post-ischemic renal tubules. This inhibition correlated with SQSTM1/p62 (sequestosome 1) aggregation and its sequestration of MAPK/ERK. SQSTM1/p62 interacted with MAPK/ERK and blocked its activation during TGFB1 treatment in autophagy-deficient tubular cells. Inhibition of MAPK/ERK suppressed EGR1 and FGF2 expression in maladaptive tubules, leading to the amelioration of renal fibrosis and improvement of renal function. These results suggest that autophagy activates MAPK/ERK in renal tubular cells, which induces EGR1 to transactivate FGF2. FGF2 is then secreted into the interstitium to stimulate fibroblasts for fibrogenesis.Abbreviation: 3-MA: 3-methyladenine; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB/β-actin: actin, beta; AKI: acute kidney injury; aa: amino acid; ATG/Atg: autophagy related; BUN: blood urea nitrogen; ChIP: chromatin immunoprecipitation; CKD: chronic kidney disease; CM: conditioned medium; COL1A1: collagen, type I, alpha 1; COL4A1: collagen, type IV, alpha 1; CQ: chloroquine; DBA: dolichos biflorus agglutinin; EGR1: early growth response 1; ELK1: ELK1, member of ETS oncogene family; FGF2: fibroblast growth factor 2; FN1: fibronectin 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAVCR1/KIM-1: hepatitis A virus cellular receptor 1; IP: immunoprecipitation; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK: mitogen-activated protein kinase; NFKB: nuclear factor kappa B; PB1: Phox and Bem1; PFT: pifithrin α; PPIB/cyclophilin B: peptidylprolyl isomerase B; RT-qPCR: real time-quantitative PCR; SQSTM1/p62: sequestosome 1; TGFB1/TGF-β1: transforming growth factor beta 1; VIM: vimentin.
| S-EPMC11135847 | biostudies-literature
Project description:Prostaglandin E2 (PGE2) has recently been recognized to play a role in immune regulation and tissue regeneration. However, the short half-life of PGE2 limits its clinical application. Improving the delivery of PGE2 specifically to the target organ with a prolonged release method is highly desirable. Taking advantage of the adequate space and proximity of the renal parenchyma, renal subcapsular delivery allows minimally invasive and effective delivery to the entire kidney. Here, we report that by covalently cross-linking it to a collagen matrix, PGE2 exhibits an adequate long-term presence in the kidney with extensive intraparenchymal penetration through renal subcapsular delivery and significantly improves kidney function. Sox9 cell lineage tracing with intravital microscopy revealed that PGE2 could activate the endogenous renal progenitor Sox9+ cells through the Yap signaling pathway. Our results highlight the prospects of utilizing renal subcapsular-based drug delivery and facilitate new applications of PGE2-releasing matrices for regenerative therapy.
| S-EPMC8554536 | biostudies-literature
Project description:A broad spectrum of lethal kidney diseases involves the irreversible destruction of the tubular structures, leading to renal function loss. Following injury, a spectrum of tissue-resident epithelial stem/progenitor cells are known to be activated and then differentiate into mature renal cells to replace the damaged renal epithelium. Here, however, we reported an alternative way that tissue-resident cells could be activated to secrete multiple factors to promote organ repair. At single-cell resolution, we showed that the resident SOX9+ renal epithelial cells (RECs) could expand in the acutely injured kidney of both mouse and human. Compared to other cells, the SOX9+ RECs overexpressed much more secretion related genes, whose functions were linked to kidney repair pathways. We also obtained long-term, feeder-free cultured SOX9+ RECs from human urine and analysed their secretory profile at both transcriptional and proteomic levels. Engraftment of cultured human SOX9+ RECs or injection of its conditional medium facilitated the regeneration of renal tubular and glomerular epithelium, probably through stimulating endogenous REC self-activation and mediating crosstalk with other renal cells. We also identified S100A9 as one of the key factors in the SOX9+ REC secretome. Altogether, the abilities to extensively propagate SOX9+ RECs in culture whilst concomitantly maintaining their intrinsic secretory capacity suggest their future application in cell-free therapies and regeneration medicine.
| S-EPMC10068929 | biostudies-literature
Project description:Purpose of reviewDespite improvements in acute kidney injury (AKI) detection, therapeutic options to halt the progression of AKI to chronic kidney disease (CKD) remain limited. In this review, we focus on recent discoveries related to the pathophysiology of the AKI to CKD continuum, particularly involving the renal tubular epithelial cells, and also discuss related ongoing clinical trials. While our focus is on injured renal tubular epithelial cells as initiators of the cascade of events resulting in paracrine effects on other cells of the kidney, the summation of maladaptive responses from various kidney cell types ultimately leads to fibrosis and dysfunction characteristic of CKD.Recent findingsRecent findings that we will focus on include, but are not limited to, characterizations of: the association between cell cycle arrest and cellular senescence in renal tubular epithelial cells and its contribution to renal fibrosis, chronic inflammation with persistent cytokine production and lymphocyte infiltration among unrepaired renal tubules, mitochondrial dysfunction and a unique role of cytosolic mitochondria DNA in fibrogenesis, prolyl hydroxylase domain proteins as potential therapeutic targets, and novel mechanisms involving the Hippo/yes-associated protein/transcriptional coactivator with PDZ-binding pathway.SummaryPotential therapeutic options to address CKD progression will be informed by a better understanding of fibrogenic pathways. Recent advances suggest additional drug targets in the various pathways leading to fibrosis.
| S-EPMC7363449 | biostudies-literature
Project description:The pathogenesis of several kidney diseases results in the eventual destruction of the renal tubular system, which can progress to end-stage renal disease. Previous studies have demonstrated the involvement of a population of SOX9-positive cells in kidney regeneration and repair process following kidney injury. However, the ability of these cells to autonomously generate kidney organoids has never been investigated. Here, we isolated SOX9+ kidney progenitor cells (KPCs) from both mice and humans and tested their differentiation potential in vitro. The data showed that the human SOX9+ KPC could self-assemble into organoids with kidney-like morphology. We also used single-cell RNA sequencing to characterize the organoid cell populations and identified four distinct types of renal tubular cells. Compared to the induced pluripotent stem cell-derived kidney organoids, KPC demonstrated more tubular differentiation potential but failed to differentiate into glomerular cells. KPC-derived organoid formation involved the expression of genes related to metanephric development and followed a similar mechanism to renal injury repair in acute kidney injury patients. Altogether, our study provided a potentially useful approach to generating kidney tubular organoids for future application.
| S-EPMC11749593 | biostudies-literature
Project description:Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulates renal peroxisome proliferator-activated receptor α signaling and restores FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing shows that renal metabolic pathways are impaired in Alport mice and activated by NR in both sexes. These transcriptional changes are confirmed by orthogonal imaging techniques and biochemical assays. Single nuclei RNA-sequencing and spatial transcriptomics, both the first of their kind from Alport mice, show that NAD+ supplementation restores FAO in proximal tubule cells. Finally, we also report, for the first time, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
2025-03-10 | GSE261872 | GEO
Project description:Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulates renal peroxisome proliferator-activated receptor α signaling and restores FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing shows that renal metabolic pathways are impaired in Alport mice and activated by NR in both sexes. These transcriptional changes are confirmed by orthogonal imaging techniques and biochemical assays. Single nuclei RNA-sequencing and spatial transcriptomics, both the first of their kind from Alport mice, show that NAD+ supplementation restores FAO in proximal tubule cells. Finally, we also report, for the first time, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
2025-03-10 | GSE261869 | GEO
Project description:Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulates renal peroxisome proliferator-activated receptor α signaling and restores FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing shows that renal metabolic pathways are impaired in Alport mice and activated by NR in both sexes. These transcriptional changes are confirmed by orthogonal imaging techniques and biochemical assays. Single nuclei RNA-sequencing and spatial transcriptomics, both the first of their kind from Alport mice, show that NAD+ supplementation restores FAO in proximal tubule cells. Finally, we also report, for the first time, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
2025-03-10 | GSE261871 | GEO