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Polyethylene glycol capped gold nanoparticles ameliorate renal ischemia-reperfusion injury in diabetic mice through AMPK-Nrf2 signaling pathway.

ABSTRACT: The aim of this study is to investigate the protective effect of polyethylene glycol capped gold nanoparticles (PEG-AuNPs) on renal ischemia-reperfusion injury (I/R)-induced acute kidney injury (AKI) in diabetic mice via the activation of adenosine 5' monophosphate-activated protein kinase-nuclear factor erythroid-2-related factor-2 (AMPK-Nrf2) pathway. Diabetes was induced in male mice (12/group) by streptozotocin (50 mg/kg) for 5 consecutive days. After 4 weeks, the mice have intravenously received doses of PEG-AuNPs (40, 150, and 400 µg/kg body weight) for 3 consecutive days, and then animals were subjected to 30 min ischemia and 48 h reperfusion. Following the treatment with three different doses of PEG-AuNPs, the levels of blood urea nitrogen (BUN) and creatinine were reduced. Obvious reduction in renal tubular atrophy, glomerular damage, mitochondrial damage, and necrotic area were ultra-structurally detected, and renal interstitial inflammation and apoptosis were diminished. Moreover, PEG-AuNPs increased the recovering of damaged renal cells, suppressed significantly levels of malondialdehyde (MDA), downregulated significantly the level of inflammatory cytokines (TNF-α and IL-1β), and upregulated the AMPK-Nrf2 pathway. PEG-AuNPs exhibited a promising alternative therapeutic target for diabetic renal I/R-induced AKI through upregulation of AMPK/PI3K/AKT path which additionally stimulated Nrf2-regulated antioxidant enzymes in a dose-dependent manner.

SUBMITTER: Saleh H

PROVIDER: S-EPMC9581836 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Polyethylene glycol capped gold nanoparticles ameliorate renal ischemia-reperfusion injury in diabetic mice through AMPK-Nrf2 signaling pathway.

Saleh Hanan H Salama Mohamed M Hussein Rehab Mohamed RM

Environmental science and pollution research international 20220610 51

The aim of this study is to investigate the protective effect of polyethylene glycol capped gold nanoparticles (PEG-AuNPs) on renal ischemia-reperfusion injury (I/R)-induced acute kidney injury (AKI) in diabetic mice via the activation of adenosine 5' monophosphate-activated protein kinase-nuclear factor erythroid-2-related factor-2 (AMPK-Nrf2) pathway. Diabetes was induced in male mice (12/group) by streptozotocin (50 mg/kg) for 5 consecutive days. After 4 weeks, the mice have intravenously rec ...[more]

PMID: 35688972

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Project description:Background Myocardial necrosis caused by myocardial ischemia-reperfusion (MI/R) in diabetic patients is prominently aggravated and can cause oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensing transcription factor that protects against myocardial ischemia/reperfusion injury (MIRI). However, the mechanism of action of Nrf2 in resveratrol-pretreated cardiomyocytes is complex. We assumed that adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/p38 mitogen-activated protein kinases (p38)/Nrf2 might be involved in resveratrol alleviating MIRI in diabetic rats as an endogenous protective mechanism. Methods A total of 50 type 2 diabetes mellitus (T2DM) rat models were randomly divided into 5 groups (n=10 in each group): sham group; MI/R group; AMPK inhibitor compound C + myocardial ischemia-reperfusion (C + MI/R) group; resveratrol + myocardial ischemia-reperfusion (RSV + MI/R) group; and resveratrol + AMPK inhibitor compound C + myocardium ischemia-reperfusion group (RSV + C + MI/R) group. Rats were fed a high fat diet, and the T2DM models were established by intraperitoneal injection of 1% streptozotocin (STZ). The MIRI models were established by ligating the left anterior descending coronary artery for 30 minutes followed by reperfusion for 120 minutes. The size of myocardial infarction was measured. Serum samples were collected to measure the concentrations of creatine kinase-MB (CK-MB). The levels of lactate dehydrogenase (LDH), glutathione (GSH), and superoxide dismutase (SOD) in myocardial tissues were determined. Immunofluorescence analysis of translocase of outer mitochondrial membrane 20 (TOMM20) was performed to observe the pathological changes in myocardial tissues. The protein expressions of AMPK, p-AMPK, p38, p-p38, Nrf2, and heme oxygenase 1 (HO-1) were determined by western blotting. Results Compared with the sham group, the expressions of AMPK, p38, Nrf2, and HO-1 in the myocardium were significantly increased in the MI/R group. Compared with the MI/R group, the RSV + MI/R group had a significantly lower oxidative stress level, milder myocardial injury, increased expressions of AMPK, Nrf2, and HO-1, and lower expression of p38. The protein expressions of Nrf2 and HO-1 were partially inhibited in the RSV + C + MI/R group. Conclusions Resveratrol can inhibit oxidative stress and alleviate MIRI by activating the AMPK/p38/Nrf2 signaling pathway. Meanwhile, AMPK/p38/Nrf2 is also an endogenous antioxidant stress pathway that protects against stress.

Project description:BackgroundIschemia-reperfusion injury (IRI) is an important cause of graft dysfunction post-liver transplantation, where donor liver with severe steatosis is more sensitive to IRI. Liver IRI involves ferroptosis and can be alleviated by heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs).AimsTo explore the role and mechanism of HO-1/BMMSCs in severe steatotic liver IRI.MethodsA severe steatotic liver IRI rat model and a hypoxia/reoxygenation (H/R) of severe steatosis hepatocyte model were established. Liver and hepatocyte damage was evaluated via liver histopathology and cell activity. Ferroptosis was evaluated through ferroptosis indexes. Nuclear factor erythroid 2-related factor 2 (Nrf2) was knocked down in severe steatotic hepatocytes. The role of Nrf2 and AMPK in HO-1/BMMSC inhibition of ferroptosis was examined using the AMP-activated protein kinase (AMPK) pathway inhibitor Compound C.ResultsThe HO-1/BMMSCs alleviated severe steatotic liver IRI and ferroptosis. HO-1/BMMSCs promoted ferritin heavy chain 1(FTH1), Nrf2, and phosphorylated (p)-AMPK expression in the H/R severe steatotic hepatocytes. Nrf2 knockdown decreased FTH1 expression levels but did not significantly affect p-AMPK expression levels. The protective effect of HO-1/BMMSCs against H/R injury in severe steatotic hepatocytes and the inhibitory effect on ferroptosis were reduced. Compound C decreased p-AMPK, Nrf2, and FTH1 expression levels, weakened the HO-1/BMMSC protective effect against severe steatotic liver IRI and H/R-injured severe steatotic hepatocytes, and reduced the inhibition of ferroptosis.ConclusionsFerroptosis was involved in HO-1/BMMSC reduction of severe steatotic liver IRI. HO-1/BMMSCs protected against severe steatotic liver IRI by inhibiting ferroptosis through the AMPK-Nrf2-FTH1 pathway. HO-1/BMMSCs activate AMPK, which activates Nrf2, promotes its nuclear transcription, then promotes the expression of its downstream protein FTH1, thereby inhibiting ferroptosis and attenuating severe steatotic liver IRI in rats. Glu: glutamic acid; Cys: cystine; GSH: glutathione; GPX4: glutathione peroxidase 4; HO-1/BMMSCs: HO-1-modified BMMSCs; Fer-1: ferrostatin-1; DFO: deferoxamine; FTH1: ferritin heavy chain1; p-AMPK: phosphorylated AMP-activated protein kinase; Nrf2: nuclear factor erythroid 2-related factor 2; IRI: ischemia-reperfusion injury; MCD: methionine-choline deficiency.

Project description:Recently, environment-friendly synthesis of gold nanoparticles (GNPs) has been extensively explored by biologists and chemists. However, significant research is still required to determine whether "eco-friendly" GNPs are beneficial to human health and to elucidate the molecular mechanisms of their effects on human cells. We used human neuronal SH-SY5Y cells to show that treatment with Kalopanacis Cortex extract-capped GNPs (KC-GNs), prepared via an eco-friendly, fast, one-pot synthetic route, protected neuronal cells against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced damage. To prepare GNPs, Kalopanacis Cortex was used without any chemical reducing and stabilizing agents. Ultraviolet-visible spectroscopy showed maximum absorbance at 526 nm owing to KC-GN surface plasmon resonance. Hydrodynamic size (54.02±2.19 nm) and zeta potential (-20.3±0.04 mV) were determined by dynamic light scattering. The average diameter (41.07±3.05 nm) was determined by high-resolution transmission electron microscopy. Energy-dispersive X-ray diffraction spectroscopy and X-ray diffraction confirmed the presence of assembled GNPs. Fourier transform infrared analysis suggested that functional groups such as O-H, C-C, and C-N participated in KC-GN formation. Cell viability assays indicated that KC-GNs restored the viability of OGD/R-treated SH-SY5Y cells. Flow cytometry demonstrated that KC-GNs inhibited the OGD/R-induced reactive oxygen species production and mitochondrial membrane potential disruption. KC-GNs also inhibited the apoptosis of OGD/R-exposed cells. Western blot analysis indicated that the OGD/R-induced cellular apoptosis and simultaneous increases in the expression of cleaved caspase-3, p53, p21, and B-cell lymphoma 2-associated X protein were reversed by KC-GNs. The KC-GN-mediated protection against OGD/R-induced neurotoxicity was diminished by NRF2 and heme oxygenase-1 gene knockdowns. Collectively, these results suggested that KC-GNs exerted strong neuroprotective effects on human neuronal cells, which might be attributed to the attenuation of OGD/R-induced neuronal cell injury through the NRF2 signaling pathway.

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Polyethylene glycol capped gold nanoparticles ameliorate renal ischemia-reperfusion injury in diabetic mice through AMPK-Nrf2 signaling pathway.

Publications

Polyethylene glycol capped gold nanoparticles ameliorate renal ischemia-reperfusion injury in diabetic mice through AMPK-Nrf2 signaling pathway.

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