Constitutive Oxidative Stress by SEPHS1 Deficiency Induces Endothelial Cell Dysfunction.
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ABSTRACT:
SUBMITTER: Jung J
PROVIDER: S-EPMC8584027 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:Environmental pollution induces oxidative stress and apoptosis in mammalian oocytes, which can cause defects in reproduction; however, the molecular regulation of oxidative stress in oocytes is still largely unknown. In the present study, we identified that dynamin-related protein 1 (DRP1) is an important molecule regulating oocyte mitochondrial function and preventing oxidative stress/apoptosis. DRP1 is a member of the dynamin GTPase superfamily localized at the mitochondrial-endoplasmic reticulum interaction site, where it regulates the fission of mitochondria and other related cellular processes. Results:Our results show that DRP1 was stably expressed during different stages of porcine oocyte meiosis, and might have a potential relationship with mitochondria as it exhibited similar localization. Loss of DRP1 activity caused failed porcine oocyte maturation and cumulus cell expansion, as well as defects in polar body extrusion. Further analysis indicated that a DRP1 deficiency caused mitochondrial dysfunction and induced oxidative stress, which was confirmed by increased reactive oxygen species levels. Moreover, the incidence of early apoptosis increased as detected by positive Annexin-V signaling. Conclusions:Taken together, our results indicate that DRP1 is essential for porcine oocyte maturation and that a DRP1 deficiency could induce mitochondrial dysfunction, oxidative stress, and apoptosis.
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Project description:Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2?, PGD?, and PGE?, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD? and PGF?? were associated with reduced eGFR, whereas 8-isoprostane and again PGF?? were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.
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