Ceria-Zirconia nanoparticles reduce intracellular globotriaosylceramide accumulation and attenuate kidney injury by enhancing the autophagy flux in cellular and animal models of Fabry disease

An, Jong Hun; Hong, Sang-Eun; Yu, Seong‐Lan; Kang, Jaeku; Park, Chang Gyo; Lee, Hoi Young; Lee, Sung Ki; Lee, Dong Chul; Park, Hwan‐Woo; Hwang, Won‐Min; Yun, Sung-Ro; Park, Yohan; Park, Moon Hyang; Yoon, Kuk Ro; Yoon, Se-Hee

doi:10.1186/s12951-022-01318-8

Cited by 11 publications

(14 citation statements)

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“…LY294002, as an autophagy inhibitor, inhibits the phosphorylation of AKT through broad-spectrum suppression of PI3K, and final achieves autophagy inhibition [ 35 ]. Some literatures have reported that autophagy retardation could aggravate glomerular diseases, suggesting that increased autophagy may attenuate MN [ 37 , 38 ]. Here, we found that LY294002 could reverse the reduction of mesangial cells proliferation and inflammation after SalB intervention.…”

Section: Discussionmentioning

confidence: 99%

Salvianolic acid B attenuates membranous nephropathy by activating renal autophagy via microRNA-145-5p/phosphatidylinositol 3-kinase/AKT pathway

Chen

Luo

et al. 2022

Bioengineered

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The abnormal proliferation and inflammatory response of the mesangial cells play a crucial role in the progression of membranous nephropathy (MN). Herein, this study aimed to investigate the therapeutic effect of Salvianolic acid B (SalB) on MN-induced mesangial abnormalities and its underlying mechanisms. MN models were established in cationic bovine serum albumin-induced Sprague-Dawley rats and lipopolysaccharide-induced human mesangial cells (HMCs). Following SalB and microRNA-145-5p antagomir treatment, kidney function was investigated by 24-hours urine protein, serum creatinine, and blood urea nitrogen. Pathological changes of kidney were investigated by Periodic acid Schiff staining. CD68 and IgG were detected by immunofluorescence in glomerulus. Mesangial autophagosomes were observed by transmission electron microscope. MicroRNA-145-5p inhibitor, mimic, LY294002, and SalB were used to treat with HMCs. In kidney and HMCs, IL-1 , IL-2, IL-6, TNF- and microRNA-145-5p was detected by quantitative real-time PCR. Phosphatidylinositol 3-kinase (PI3K), phosphorylated AKT, AKT, beclin1, and microtubule-associated protein light chain 3 (LC3) levels were detected by Western blot. HMCs proliferation and cycle were detected by Cell Counting Kit-8 and flow cytometry. LC3 were detected by LC3-dual-fluorescent adenovirus in HMCs. Our results showed that SalB significantly ameliorated kidney function and pathological changes. Furthermore, it significantly alleviated proliferation, inflammation and activated autophagy in mesangial cells. Moreover, microRNA-145-5p antagomir accentuated MN while microRNA-145-5p inhibitor and LY294002 encouraged proliferation and inflammation through PI3K/AKT pathway in HMCs. Collectively, our study demonstrated that SalB activated renal autophagy to reduce cell proliferation and inflammation of MN, which was mediated by microRNA-145-5p to inhibit PI3K/AKT pathway, and ultimately attenuated MN.

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Section: Discussionmentioning

confidence: 99%

Salvianolic acid B attenuates membranous nephropathy by activating renal autophagy via microRNA-145-5p/phosphatidylinositol 3-kinase/AKT pathway

Chen

Luo

et al. 2022

Bioengineered

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“…The PEG–CZNPs were synthesized following a previous report. , Briefly, 5 mL of the CZNPs sample in chloroform (10 mg/mL) was blended with 4 mL of 18:0 PEG2000 PE (contains: chloroform). The majority of the chloroform was then removed using a rotary evaporator, and the sample was incubated at 80 °C for 2 h in a vacuum oven to ensure complete solvent removal.…”

Section: Methodsmentioning

confidence: 99%

“…After cooling, 3 mL of nitric acid and 0.5 mL of hydrofluoric acid were added for a further overnight incubation at 150 °C. The vessel lid was then opened and heated to dryness, followed by adding 10 g of 1% nitric acid solution for ICP-MS measurement …”

Section: Methodsmentioning

confidence: 99%

“…It is worth noting that the authors' previous study utilized a cellular model of FD generated by siRNA transfection of αGLA and examined changes in cells after 8 days of transfection. 16 In contrast, this study employed a cellular model created using shRNA of αGLA and investigated changes over a relatively long period after transfection. This extended time frame allows for the observation of not only intracellular GB3 accumulation but also the progression of fibrotic changes in cells.…”

Section: Peg−cznps Reduce Intracellular Gb3 Accumulation and Ameliora...mentioning

confidence: 99%

“…Additionally, when NPs are coated with polyethylene glycol (PEG), it enhances water dispersibility by its hydrophilic behavior and improves the targeting delivery capability . In a previous study, the authors reported that PEG–CZNPs enhanced autophagy flux and reduced intracellular accumulation of GB3 in both cellular and animal models of FD . However, the mechanism underlying the enhancement of autophagy flux was not known, and the long-term effects in vitro and in vivo of NPs have not been explored; therefore, the treatment efficacy and toxicity of NPs are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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PEG-Capped Ceria–Zirconia Nanoparticles Improved Renal Fibrosis In Cellular and Animal Models of Fabry Disease

Kim,

Hong,

et al. 2024

ACS Appl. Nano Mater.

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Fabry disease (FD) is an X-linked hereditary disorder that results in the malfunction of α-galactosidase A (αGLA), leading to the accumulation of globotriaosylceramide (GB3) in cells and causing organ damage. This condition induces several pathological intracellular signaling pathways, with the dysfunction in autophagy being a crucial component. Phospholipid−polyethylene glycol-capped Ceria−Zirconia antioxidant nanoparticles (PEG−CZNPs) have been reported to enhance autophagy flux. This study aims to assess the mechanisms of action of PEG−CZNPs in autophagy regulation and examine their effects on chronic kidney injury in cellular and animal models of FD. A stable cellular model of FD was successfully created through the shRNA transfection of αGLA. PEG−CZNPs were found to enhance autophagy flux by translocating Transcription factor EB (TFEB) to the nucleus. To demonstrate TFEB's importance in autophagy flux by PEG−CZNPs, HK-2 cells were transfected with siTFEB. Autophagy flux significantly decreased after the knockdown of TFEB, despite PEG−CZNPs treatment. We next assessed the upper signaling pathway of TFEB by PEG−CZNPs. TFEB dephosphorylation was significantly influenced by the Akt/GSK3ß signaling pathway in response to PEG−CZNPs. PEG−CZNPs successfully reduced intracellular GB3 accumulation and decreased fibrous markers such as α-smooth muscle actin (αSMA), collagen type IV (ColIV), and matrix metallopeptidase 9 (MMP9) expression in the cellular model of FD. To evaluate the impact of PEG−CZNPs on kidney injury in a mouse model of FD, saline or PEG−CZNPs (10 mg/kg/day) were administered intraperitoneally twice per week for 24 or 48 weeks, starting at the age of 4 weeks. PEG−CZNPs significantly reduced both GB3 accumulation and αSMA expression in the kidneys. In conclusion, these results suggest that PEG− CZNPs promote autophagy flux through the Akt/GSK3β-TFEB signaling pathway and demonstrate a beneficial effect on kidney fibrosis and intracellular GB3 reduction in cellular and animal models of FD. These results provide valuable insights into potential therapeutics for FD.

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The impact of nanomaterials on autophagy across health and disease conditions

Florance,

Cordani,

Pashootan

et al. 2024

Cell. Mol. Life Sci.

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Autophagy, a catabolic process integral to cellular homeostasis, is constitutively active under physiological and stress conditions. The role of autophagy as a cellular defense response becomes particularly evident upon exposure to nanomaterials (NMs), especially environmental nanoparticles (NPs) and nanoplastics (nPs). This has positioned autophagy modulation at the forefront of nanotechnology-based therapeutic interventions. While NMs can exploit autophagy to enhance therapeutic outcomes, they can also trigger it as a pro-survival response against NP-induced toxicity. Conversely, a heightened autophagy response may also lead to regulated cell death (RCD), in particular autophagic cell death, upon NP exposure. Thus, the relationship between NMs and autophagy exhibits a dual nature with therapeutic and environmental interventions. Recognizing and decoding these intricate patterns are essential for pioneering next-generation autophagy-regulating NMs. This review delves into the present-day therapeutic potential of autophagy-modulating NMs, shedding light on their status in clinical trials, intervention of autophagy in the therapeutic applications of NMs, discusses the potency of autophagy for application as early indicator of NM toxicity. Graphical Abstract

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Ceria-Zirconia nanoparticles reduce intracellular globotriaosylceramide accumulation and attenuate kidney injury by enhancing the autophagy flux in cellular and animal models of Fabry disease

Cited by 11 publications

References 62 publications

Salvianolic acid B attenuates membranous nephropathy by activating renal autophagy via microRNA-145-5p/phosphatidylinositol 3-kinase/AKT pathway

Salvianolic acid B attenuates membranous nephropathy by activating renal autophagy via microRNA-145-5p/phosphatidylinositol 3-kinase/AKT pathway

PEG-Capped Ceria–Zirconia Nanoparticles Improved Renal Fibrosis In Cellular and Animal Models of Fabry Disease

The impact of nanomaterials on autophagy across health and disease conditions

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