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The Prospective Ameliorative Role of Zinc Oxide Nanoparticles in STZ-Induced Diabetic Nephropathy in Rats: Mechanistic Targeting of Autophagy and Regulating Nrf2/TXNIP/NLRP3 Inflammasome Signaling

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Abstract

Diabetic nephropathy (DN) as one of the common microvascular complications of diabetes mellitus, is the main cause of end-stage renal disease. Zinc oxide nanoparticles (ZnO NPs) have been employed in several biomedical aspects. This study purposed to explore the mechanistic renoprotective effects of ZnO NPs in STZ-induced DN. Sixty male Wistar rats were allocated into four equal groups: control, ZnO NPs control, STZ, and STZ + ZnO NPs groups. At the end of the experiment, blood and urine biochemical parameters were assayed. Renal tissue level of advanced glycation end products (AGEs) was assayed spectrofluorometrically, moreover, nuclear factor erythroid 2–related factor 2 (Nrf2) DNA-binding activity and IL-1β levels were detected by ELISA. The gene expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor family pyrin domain containing 3 (NLRP3) were detected by quantitative real-time PCR. Oxidative stress markers were determined spectrophotometrically. Also, renal tissue histopathological and immunohistochemical analyses were determined. After 6 weeks of treatment, ZnO NPs markedly improved the biochemical, renal functions, and histopathological findings. Furthermore, ZnO NPs significantly increased Nrf2-DNA-binding activity and downregulated TXNIP gene expression leading to restoration of the redox status. Additionally, ZnO NPs ameliorated AGEs levels, enhanced autophagy activity, and attenuated inflammasome activation via downregulation of NLRP3 expression and reducing IL-1β levels. Based on our results, we concluded that ZnO NPs can be considered as a promising agent for slowing the progression of DN via interplay between autophagy and Nrf2/TXNIP/NLRP3 inflammasome signaling.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

DN:

Diabetic nephropathy

Nrf2:

Nuclear factor erythroid 2–related factor 2

TXNIP:

Thioredoxin-interacting protein

NLRP3:

NOD-like receptor family pyrin domain containing 3

ROS:

Reactive oxygen species

ZnO NPs:

Zinc oxide nanoparticles

STZ:

Streptozotocin

FBG:

Fasting blood glucose

AGEs:

Advanced glycation end products

MDA:

Malondialdehyde

SOD:

Superoxide dismutase

ARE:

Antioxidant response element

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Authors and Affiliations

  1. Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Sarah Ragab Abd El-Khalik & Hanem Rabah

  2. Medical Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Elham Nasif

  3. Anatomy Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Heba M. Arakeep

Authors
  1. Sarah Ragab Abd El-Khalik
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  2. Elham Nasif
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  3. Heba M. Arakeep
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  4. Hanem Rabah
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Contributions

Sarah Ragab: conceptualization, project administration, methodology, supervision, visualization, data curation, writing—original draft, writing—review and editing. Elham Nasif: validation, writing—review and editing. Heba Arakeep: methodology, formal analysis, visualization, writing—review and editing. Hanem Rabah: project administration, methodology, investigation, data curation, visualization, writing—original draft.

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Correspondence to Sarah Ragab Abd El-Khalik.

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This study was done in accordance with the guiding ethics of the Ethical Committee of Medical Research, Faculty of Medicine, Tanta University, Egypt.

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The authors declare no competing interests.

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Abd El-Khalik, S.R., Nasif, E., Arakeep, H.M. et al. The Prospective Ameliorative Role of Zinc Oxide Nanoparticles in STZ-Induced Diabetic Nephropathy in Rats: Mechanistic Targeting of Autophagy and Regulating Nrf2/TXNIP/NLRP3 Inflammasome Signaling. Biol Trace Elem Res 200, 1677–1687 (2022). https://doi.org/10.1007/s12011-021-02773-4

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