Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis.
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ABSTRACT:
SUBMITTER: Miguel V
PROVIDER: S-EPMC7919728 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Chronic kidney disease (CKD) is characterized by the progressive and irreversible deterioration of kidney function and structure with the appearance of renal fibrosis. A significant decrease in mitochondrial metabolism, specifically a reduction in fatty acid oxidation (FAO) in tubular cells, is observed in tubulointerstitial fibrosis, whereas FAO enhancement provides protection. Untargeted metabolomics offers the potential to provide a comprehensive analysis of the renal metabolome in the context of kidney injury. Methodology: Renal tissue from a carnitine palmitoyl transferase 1a (Cpt1a) overexpressing mouse model, which displays enhanced FAO in the renal tubule, subjected to folic acid nephropathy (FAN) was studied through a multiplatform untargeted metabolomics approach based on LC-MS, CE-MS and GC-MS analysis to achieve the highest coverage of the metabolome and lipidome affected by fibrosis. The expression of genes related to the biochemical routes showing significant changes was also evaluated. Results: By combining different tools for signal processing, statistical analysis and feature annotation, we were able to identify variations in 194 metabolites and lipids involved in many metabolic routes: TCA cycle, polyamines, one-carbon metabolism, amino acid metabolism, purine metabolism, FAO, glycerolipids and glycerophospholipids synthesis and degradation, glycosphingolipids interconversion, and sterol metabolism. We found several metabolites strongly altered by FAN, with no reversion induced by Cpt1a overexpression (v.g. citric acid), whereas other metabolites were influenced by CPT1A-induced FAO (v.g. glycine-betaine). Conclusion: It was implemented a successful multiplatform metabolomics approach for renal tissue analysis. Profound metabolic changes accompany CKD-associated fibrosis, some associated with tubular FAO failure. These results highlight the importance of addressing the crosstalk between metabolism and fibrosis when undertaking studies attempting to elucidate the mechanism of CKD progression. Graphical Abstract
| S-EPMC10291237 | biostudies-literature
Project description:The latest progress in the field of renal fibrosis mainly focuses on the new concept of "partial epithelial-mesenchymal transition (pEMT)" to explain the contribution of renal tubular epithelial (RTE) cells to renal fibrosis and the crucial role of fatty acid oxidation (FAO) dysfunction in RTE cells for the development of renal fibrosis. FAO depression is considered to be secondary or occur simultaneously with pEMT. We explored the relationship between pEMT and FAO and the effect of rhein on them. Intragastric administration of rhein significantly improved the levels of BUN, Scr, α-SMA, collagen 1A and histopathological changes in UUO-rats. Transcriptomic and metabolomic analyses revealed that abnormal signaling pathways were involved in EMT and FAO disorders. RTE cell experiments showed that TGF-β could inhibit the activity of Cpt1a, resulting in ATP depletion and lipid deposition. Cpt1a inhibitor induced EMT, while Cpt1 substrate or rhein inhibited EMT, indicating that Cpt1a-mediated FAO dysfunction is essential for RTE cells EMT. Further studies showed that Cpt1a activity were regulated by SirT1/STAT3/Twist1 pathway. Rhein inhibits RTE cell EMT by promoting Cpt1a-mediated FAO through the SirT1/STAT3/Twist1 pathway. Surprisingly and importantly, our experiments showed that FAO depression occurs before EMT, and EMT is one of the results of FAO depression.
| S-EPMC9000220 | biostudies-literature
Project description:To compare the transcriptional profile in renal tubules conditional deletion of Cpt1a, to floxed littermate controls.
2024-03-01 | GSE246150 | GEO
Project description:BackgroundRenal fibrosis is a common pathological process of chronic kidney diseases induced by multiple factors. Hypoxic pretreatment of mesenchymal stem cells can enhance the efficacy of secreted extracellular vesicles (MSC-EVs) on various diseases, but it is not clear whether they can better improve renal fibrosis. The latest research showed that recovery of fatty acid oxidation (FAO) can reduce renal fibrosis. In this study, we aimed to examine whether hypoxic pretreatment with MSC extracellular vesicles (Hypo-EVs) can improve FAO to restore renal fibrosis and to investigate the underlying mechanism.MethodsHypo-EVs were isolated from hypoxia-pretreated human placenta-derived MSC (hP-MSC), and Norm-EVs were isolated from hP-MSC cultured under normal conditions. We used ischemia-reperfusion (I/R)-induced renal fibrosis model in vivo. The mice were injected with PBS, Hypo-EVs, or Norm-EVs immediately after the surgery and day 1 postsurgery. Renal function, kidney pathology, and renal fibrosis were assessed for kidney damage evaluation. For mechanistic exploration, fatty acid oxidation (FAO), mitochondrial morphological alterations, ATP production and mitochondrial mass proteins were detected in vivo. Mitochondrial membrane potential and reactive oxygen species (ROS) production were investigated in vitro.ResultsWe found that Hypo-EVs confer a superior therapeutic effect on recovery of renal structure damage, restoration of renal function and reduction in renal fibrosis. Meanwhile, Hypo-EVs enhanced mitochondrial FAO in kidney by restoring the expression of a FAO key rate-limiting enzyme carnitine palmitoyl-transferase 1A (CPT1A). Mechanistically, the improvement of mitochondrial homeostasis, characterized by repaired mitochondrial structure, restoration of mitochondrial mass and ATP production, inhibition of oxidative stress, and increased mitochondrial membrane potential, partially explains the effect of Hypo-EVs on improving mitochondrial FAO and thus attenuating I/R damage.ConclusionsHypo-EVs suppress the renal fibrosis by restoring CPT1A-mediated mitochondrial FAO, which effects may be achieved through regulation of mitochondrial homeostasis. Our findings provide further mechanism support for development cell-free therapy of renal fibrosis.
| S-EPMC9080148 | biostudies-literature
Project description:Polybrominated diphenyl ethers (PBDEs)-induced neurotoxicity is closely associated with mitochondrial abnormalities. Mitochondrial fusion and fission dynamics are required for the maintenance of mitochondrial homeostasis. However, little is known about how PBDEs disrupt this dynamics and whether such disruption contributes to impaired neurodevelopment. Methods: We investigated the effects of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47), the dominant congener in human samples, on mitochondrial fusion and fission dynamics using PC12 cells, a well-defined in vitro neurodevelopmental model. We also evaluated the effects of perinatal low-dose PBDE-47 exposure on hippocampal mitochondrial dynamics and its association with neurobehavioral changes in adult Sprague-Dawley rats. Results: In vitro, PBDE-47 disrupted mitochondrial dynamics by inhibiting mitochondrial fusion and fission simultaneously, accompanied by mitochondrial fragmentation, membrane potential dissipation, ATP loss, and apoptosis activation. Specifically, enhancing mitochondrial fusion by the chemical promoter M1 or adenovirus-mediated mitofusin 2 (Mfn2) overexpression rescued PBDE-47-caused mitochondrial dynamic, morphological and functional impairments, prevented the resultant apoptosis and promoted neuronal survival. Unexpectedly, either stimulating mitochondrial fission by adenovirus-mediated fission protein 1 (Fis1) overexpression or suppressing mitochondrial fission by the mitochondrial division inhibitor-1 (Mdivi-1) failed to reverse whereas aggravated PBDE-47-induced mitochondrial damage and neuronal death. Importantly, promoting mitochondrial fusion by Mfn2 overexpression neutralized the detrimental effects elicited by Fis1 overexpression after PBDE-47 treatment. Finally, perinatal oral administration of PBDE-47 elicited neurobehavioral deficits and hippocampal neuronal loss via apoptosis in adult rats, which were associated with mitochondrial dynamics alterations manifested as a fragmented phenotype. Conclusion: Our results suggest that PBDE-47 disrupts mitochondrial dynamics to induce mitochondrial abnormalities, triggering apoptosis and thus contributing to neuronal loss and subsequent neurobehavioral deficits. Targeting mitochondrial fusion may be a promising therapeutic intervention against PBDE-47 neurotoxicity.
| S-EPMC6956817 | biostudies-literature
Project description:Increasing evidence indicates that obesity is highly associated with chronic kidney disease (CKD). GLP-1 receptor (GLP-1R) agonist has shown benefits on kidney diseases, but its direct role on kidney metabolism in obesity is still not clear. This study aims to investigate the protection and metabolic modulation role of liraglutide (Lira) on kidney of obesity. Rats were induced obese by high-fat diet (HFD), and renal function and metabolism changes were evaluated by metabolomic, biological and histological methods. HFD rats exhibited systemic metabolic disorders such as obesity, hyperlipidemia and impaired glucose tolerance, as well as renal histological and function damages, while Lira significantly ameliorated these adverse effects in HFD rats. Metabolomic data showed that Lira directly reduced renal lipids including fatty acid residues, cholesterol, phospholipids and triglycerides, and improved mitochondria metabolites such as succinate, citrate, taurine, fumarate and nicotinamide adenine dinucleotide (NAD+) in the kidney of HFD rats. Furthermore, we revealed that Lira inhibited renal lipid accumulation by coordinating lipogenic and lipolytic signals, and partly rescued renal mitochondria function via Sirt1/AMPK/PGC1α pathways in HFD rats. This study suggested that Lira alleviated HFD-induced kidney injury at least partly via directly restoring renal metabolism, thus GLP-1R agonist is a promising therapy for obesity-associated CKD.
| S-EPMC5873987 | biostudies-literature
Project description:NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1? and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD(cl1)) cell line increased TGF-?1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1? and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions.
| S-EPMC3507365 | biostudies-literature
Project description:Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24 mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases.
| S-EPMC4854554 | biostudies-literature
Project description:Introduction: Renal interstitial fibrosis is a common pathophysiological change in the chronic kidney disease (CKD). Nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin 6 (SIRT6) is demonstrated to protect against kidney injury. Vitamin B3 is the mostly used form of NAD precursors. However, the role of SIRT6 overexpression in renal interstitial fibrosis of CKD and the association between dietary vitamin B3 intake and renal function remain to be elucidated. Methods: Wild-type (WT) and SIRT6-transgene (SIRT6-Tg) mice were given with high-adenine diets to establish CKD model. HK2 cells were exposed to transforming growth factor β1 (TGF-β1) in vitro to explore related mechanism. Population data from Multi-Ethnic Study of Atherosclerosis (MESA) was used to examine the association between dietary vitamin B3 intake and renal function decline. Results: Compared to WT mice, SIRT6-Tg mice exhibited alleviated renal interstitial fibrosis as evidenced by reduced collagen deposit, collagen I and α-smooth muscle actin expression. Renal function was also improved in SIRT6-Tg mice. Homeodomain interacting protein kinase 2 (HIPK2) was induced during the fibrogenesis in CKD, while HIPK2 was downregulated after SIRT6 overexpression. Further assay in vitro confirmed that SIRT6 depletion exacerbated epithelial-to-mesenchymal transition of HK2 cells, which might be linked with HIPK2 upregulation. HIPK2 was inhibited by SIRT6 in the post-transcriptional level. Population study indicated that higher dietary vitamin B3 intake was independently correlated with a lower risk of estimate glomerular filtration rate decline in those ≥65 years old during follow-up. Conclusion: SIRT6/HIPK2 axis serves as a promising target of renal interstitial fibrosis in CKD. Dietary vitamin B3 intake is beneficial for renal function in the old people.
| S-EPMC9510922 | biostudies-literature
Project description:BackgroundDespite the dramatic advances in modern medicine, efficient therapeutic measures for renal fibrosis remain limited. Celastrol (CLT) is effective in treating renal fibrosis in rat models, while causing severe systemic toxicity. Thus, we designed a tubule-specific nanocage (K3-HBc NCs) that effectively deliver CLT to tubular epithelial cell in a virus-like manner. The targeting ligand (K3) to tubular epithelial cells was displayed on the surface of Hepatitis B core protein (HBc) NCs by genetic fusion to the major immunodominant loop region. Ultra-small CLT nanodots were subtly encapsulated into the cavity through electrostatic interaction with the disassembly and reassembly of K3-HBc NCs, to yield K3-HBc/CLT complex. The efficacy of K3-HBc/CLT NCs were demonstrated in Unilateral ureteral obstruction (UUO)-induced renal fibrosis.ResultsThe self-assembled K3-HBc/CLT could specifically target tubular epithelial cells via affinity with K3 ligand binding to the megalin receptor, significantly attenuating renal fibrosis. Remarkably, K3-HBc/CLT NCs significantly increased therapeutic efficacy and reduced the systemic toxicity in comparison with free CLT in UUO-induced mouse renal fibrosis model. Importantly, analysis of RNA sequencing data suggested that the anti-fibrotic effect of K3-HBc/CLT could be attributed to suppression of premature senescence in tubular epithelial cells via p21Cip1 and p16Ink4a pathway.ConclusionThe tubule-specific K3-HBc/CLT represented a promising option to realize precise treatment for renal fibrosis.
| S-EPMC8157627 | biostudies-literature