Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA319496 | ENA |
REPOSITORIES: ENA
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Project description:The kidney has a high energy demand and is dependent on oxidative metabolism for ATP production. Accordingly, the kidney is rich in mitochondria, and mitochondrial dysfunction is a common denominator for several renal diseases. While the mitochondrial master regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is highly expressed in kidney, its role in renal physiology is so far unclear. Here we show that PGC-1α is a central transcriptional regulator of mitochondrial metabolic pathways in the kidney. Moreover we demonstrate that mice with an inducible nephron-specific inactivation of PGC-1α in the kidney display elevated urinary sodium excretion, exacerbated renal steatosis during metabolic stress but normal blood pressure regulation. Overall, PGC-1α seems largely dispensable for basal renal physiology. However, the central role of PGC-1α in renal mitochondrial biogenesis indicates that activation of PGC-1α in the context of renal disorders could be a valid therapeutic strategy to ameliorate renal mitochondrial dysfunction.
2016-04-26 | GSE80618 | GEO
Project description:Endothelial cell (EC) injury plays a critical part in the occurrence and progression of renal ischemia-reperfusion injury (IRI). PGC-1α, as a master regulator of mitochondrial function, has been identified as a potential therapeutic target for treating injured ECs. Here, fucoidan-plasmid PGC-1α-gas vesicles (Fuc-pPGC-1α-GVs) are synthesized to identify damaged renal ECs at the early stage of renal IRI through the high affinity of fucoidan to P-selectin, and significantly enhance gene transfection efficiency by ultrasound-mediated controlled cavitation, resulting in specific overexpression of PGC-1α in injured renal ECs. In vitro and in vivo evidence reveals that ultrasound-mediated gene transfection with Fuc-pPGC-1α-GVs could ameliorate renal IRI by rescuing the function of ECs, decreasing immune cells infiltration, and alleviating renal tubular injury. Mechanistically, overexpressed PGC-1α in injured renal ECs promotes mitophagy and inhibits ROS production by upregulating BNIP3, BNIP3L and SOD2. This study provides a promising strategy for early and efficient treatment of renal IRI.
2025-05-06 | GSE296143 | GEO
Project description:Recent evidence suggest that the circadian timing system plays an important role in the control of renal function and maintaining blood pressure. Here, we analyzed circadian rhythms of urinary excretion of sodium and potassium in wild-type mice and mice lacking circadian transcriptional activator clock. Analysis of urines collected at hourly intervals over a 24-hour period revealed dramatic changes in rhythms of sodium and potassium excretion in clock(-/-) mice. In parallel, significant differences in circadian pattern of plasma aldosterone levels, but not in the 24-hour mean aldosterone levels, were observed. Microarray-based profiling of renal transcriptomes demonstrated that clock(-/-) mice exhibit dysregulation in multiple mechanisms involved in maintaining sodium and potassium balance by the kidney. The most significant changes were detected in the expression levels of several key enzymes (Cyp4a14, Cyp4a12a and Cyp4a12b) required for the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a powerful regulator of renal sodium and potassium excretion, renal vascular tone and blood pressure. The 20-HETE levels measured in kidney microsomes of wild-type mice followed a circadian-like temporal pattern. In clock(-/-) mice, the acrophase of this rhythm was shifted by 8 hours and the 24-hour mean levels of 20-HETE were significantly decreased. These results demonstrate that circadian rhythms of urine electrolyte excretion are largely dependent on the circadian clock activity and indicate that circadian oscillations in renal 20-HETE content could be an important mechanism of blood pressure regulation.
2012-04-30 | GSE27366 | GEO
Project description:PGC-1α plays a central role in maintaining the mitochondrial and energy metabolism homeostasis, linking external stimuli to the transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however potential RNA-processing role(s) have remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export factor NXF1. Inducible depletion of endogenous PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrate that the RNA-binding activity is required for nuclear export of co-activated transcripts and mitochondrial homeostasis. Moreover, a quantitative proteomics approach confirmed PGC-1α-dependent RNA transport and mitochondrial-related functions, identifying also novel mRNA nuclear export targets in age-related telomere maintenance. Discovering a novel function for a major cellular homeostasis regulator provides new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing and neurodegenerative diseases.
2023-09-06 | PXD031189 | Pride
Project description:Patients with sepsis often experience severe renal dysfunction and damage and accelerate to end-stage renal failure with high mortality, which currently lacks effective therapeutic approaches. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, has been proven to have therapeutic properties for a variety of acute and chronic inflammatory diseases. However, the role of GDF11 in sepsis-associated acute kidney injury (SAKI) remains elusive. Here, we aimed to investigate the role of GDF11 in SAKI and identify the signaling pathways modulated by GDF11. In a mouse model of cecal ligation and puncture (CLP)-induced SAKI, GDF11 was found to be highly expressed in tubular epithelial cells and macrophages in the kidney. Moreover, gene silencing of GDF11 using adeno-associated virus (AAV) aggravated renal dysfunction, increased tubular damage, and augmented renal apoptosis in CLP-induced SAKI mice. In contrast, replenishment of recombinant GDF11 (rGDF11) significantly mitigated these adverse effects. Further investigation revealed that GDF11 activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidative pathways, mainly through induction of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α expression, which, in turn, inhibited overactivated inflammation and coagulation both in vivo and in vitro. Additionally, these beneficial effects of GDF11 were largely diminished by AAV-mediated PGC-1α knockdown and depletion of Nrf2 in CLP-induced SAKI mice. Overall, these findings demonstrate that GDF11 represents a promising therapeutic approach for SAKI and reveal the important role of PGC-1α/Nrf2 signaling in GDF11-mediated renal protection during SAKI.
2025-09-03 | GSE297658 | GEO
Project description:Recent evidence suggest that the circadian timing system plays an important role in the control of renal function and maintaining blood pressure. Here, we analyzed circadian rhythms of urinary excretion of sodium and potassium in wild-type mice and mice lacking circadian transcriptional activator clock. Analysis of urines collected at hourly intervals over a 24-hour period revealed dramatic changes in rhythms of sodium and potassium excretion in clock(-/-) mice. In parallel, significant differences in circadian pattern of plasma aldosterone levels, but not in the 24-hour mean aldosterone levels, were observed. Microarray-based profiling of renal transcriptomes demonstrated that clock(-/-) mice exhibit dysregulation in multiple mechanisms involved in maintaining sodium and potassium balance by the kidney. The most significant changes were detected in the expression levels of several key enzymes (Cyp4a14, Cyp4a12a and Cyp4a12b) required for the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a powerful regulator of renal sodium and potassium excretion, renal vascular tone and blood pressure. The 20-HETE levels measured in kidney microsomes of wild-type mice followed a circadian-like temporal pattern. In clock(-/-) mice, the acrophase of this rhythm was shifted by 8 hours and the 24-hour mean levels of 20-HETE were significantly decreased. These results demonstrate that circadian rhythms of urine electrolyte excretion are largely dependent on the circadian clock activity and indicate that circadian oscillations in renal 20-HETE content could be an important mechanism of blood pressure regulation. We examined the temporal profiles of gene expression in mouse whole kidney. Animals were sacrificed for microdissection every 4 hours, i.e. at ZT0, ZT4, ZT8, ZT12, ZT16 and ZT20 (ZT M-bM-^@M-^S Zeitgeber (circadian) time, indicates time of light-on as ZT0 and time of light-off as ZT12). The microarray hybridization was performed in duplicates on pools of RNA composed of equivalent amounts of RNA prepared from teo or three animals at each ZT time-point.
2012-04-29 | E-GEOD-27366 | biostudies-arrayexpress
Project description:Acute kidney injury (AKI) is rapidly increasing and becomes a major of public health problem nowadays. However, its underlying mechanism has not been elucidated. Studies have shown that cluster of differentiation-44 (CD44) play a role in the pathological process of AKI. Nevertheless, the molecule mechanism has not been totally clarified. Herein, we found that CD44 is increased in renal tubules in ischemia-reperfusion injury (IRI)-induced AKI mice. Knockout of CD44 improved mitochondrial biogenesis and mitochondrial fatty acid oxidation (FAO), further protecting against renal tubular cell apoptosis and kidney injury. Conversely, ectopic expression of CD44 impaired mitochondrial function and FAO, which exacerbated the pathological process of AKI. Transcriptome sequencing revealed NF-κB p65 is highly responsible for this process. In vitro, we found that CD44 induced activation of NF-κB p65 via mitogen-activated protein kinase (MAPK) ERK1/2 and MAPK p38, further transcriptionally silencing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoters. As a result, downregulation of PGC-1α contributed to impairment of mitochondrial dysfunction and FAO, resulting in the deterioration of AKI. Our study found that inhibiting CD44 is a new potential therapeutic strategy for AKI through promoting mitochondrial biogenesis and FAO. The underlying mechanism is associated with MAPK/p65/ PGC-1α pathway.
2025-02-26 | GSE252060 | GEO
Project description:PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however the potential RNA-processing function(s) remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrated that its RNA/NXF1-binding activity is required for the nuclear exportof a subset of mRNAsand mitochondrial homeostasis.Genome-wide investigations revealed that the nuclear export function is not strictly linked to PGC-1α-binding promoters, identifyingin turnnovel mRNA nuclear export targets inmRNA- and age-related pathways.These findingsprovide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing andneurodegeneration.
2023-07-19 | GSE230413 | GEO
Project description:PGC-1α plays a central role in maintaining mitochondrial and energy metabolism homeostasis, linking external stimuli to transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however the potential RNA-processing function(s) remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1α directly interacts with RNA and the nuclear RNA export receptor NXF1. Inducible depletion of PGC-1α and expression of RNAi-resistant RS-deleted PGC-1α further demonstrated that its RNA/NXF1-binding activity is required for the nuclear exportof a subset of mRNAsand mitochondrial homeostasis.Genome-wide investigations revealed that the nuclear export function is not strictly linked to PGC-1α-binding promoters, identifyingin turnnovel mRNA nuclear export targets inmRNA- and age-related pathways.These findingsprovide new directions to further elucidate the roles of PGC-1α in gene expression, metabolic disorders, ageing andneurodegeneration.
2023-07-19 | GSE230428 | GEO
Project description:Sickle cell disease-induced nephropathy (SCN) is a leading cause of morbidity and mortality in sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on non-specific tests and may not detect SCN until renal damage has become irreversible. Therefore, specific biomarkers for early diagnosis of SCN are urgently needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic proteins, reflecting the physiological and pathophysiological states of the kidney. Using proteomics, we analyzed the proteomes of urinary exosomes from 5 humanized SCD mice (Townes model) at 2 months (without albuminuria) and 4 months (with albuminuria) of age. We found that excretion of 166 proteins was significantly increased and 174 proteins was significantly decreased in the exosomes when mice developed albuminuria. Based on the relevance to SCD, chronic kidney disease and Western confirmation in mice, we analyzed protein abundance of heparanase, cathepsin C, α2-macroglobulin and SERCA3 in the urinary exosomes and urine of 18 SCD patients without albuminuria and 12 patients with albuminuria using Western analyses. We found that increased excretion of these proteins in the urinary exosomes and urine correlated with albuminuria in the patients. Furthermore, excretion of heparanase, cathepsin C, and α2-macroglobulin in the urinary exosomes correlated with their excretion in the urine and urinary albumin creatinine ratio. In conclusion, our results suggest that heparanase, cathepsin C, α2-macroglobulin and SERCA3 could serve as specific and reliable biomarkers for early detection of SCN.
2024-02-07 | PXD043401 | JPOST Repository