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Cited by 135Acute Kidney Injury ResearchCircadian rhythm and melatoninChronic Kidney Disease and Diabetes

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Melatonin attenuates acute kidney ischemia/reperfusion injury in diabetic rats by activation of the SIRT1/Nrf2/HO-1 signaling pathway

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Shi, Si, Lei, Shaoqing, Tang, Chaoliang, Wang, Kai, Xia, Zhongyuan·2019·Bioscience Reports
DOI 10.1042/bsr20181614PMC PMC6331666
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Abstract

Background and aims: Diabetic kidney is more sensitive to ischemia/reperfusion (I/R) injury, which is associated with increased oxidative stress and impaired nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Melatonin, a hormone that is secreted with the rhythm of the light/dark cycle, has antioxidative effects in reducing acute kidney injury (AKI). However, the molecular mechanism of melatonin protection against kidney I/R injury in the state of diabetes is still unknown. In the present study, we hypothesized that melatonin attenuates renal I/R injury in diabetes by activating silent information regulator 2 associated protein 1 (SIRT1) expression and Nrf2/HO-1 signaling. Methods: Control or streptozotocin (STZ)-induced Type 1 diabetic rats were treated with or without melatonin for 4 weeks. Renal I/R injury was achieved by clamping both left and right renal pedicles for 30 min followed by reperfusion for 48 h. Results: Diabetic rats that were treated with melatonin undergoing I/R injury prevented renal injury from I/R, in aspects of the histopathological score, cell apoptosis, and oxidative stress in kidney, accompanied with decreased expressions of SIRT1, Nrf2, and HO-1 as compared with those in control rats. All these alterations were attenuated or prevented by melatonin treatment; but these beneficial effects of melatonin were abolished by selective inhibition of SIRT1 with EX527. Conclusion: These findings suggest melatonin could attenuate renal I/R injury in diabetes, possibly through improving SIRT1/Nrf2/HO-1 signaling.

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Figure 1 A diabetic model of adult male SD rats was induced using STZ All rats were subjected to sham surgery or bilateral renal I/R injury. (A) Renal Hematoxylin and Eosin staining. Magnification: 200×. The lower panels are the magnified images of the boxed areas in the upper panels. (B) TUNEL staining. Magnification: 400×. (C) Histopathological scoring. (D) TUNEL assay apoptosis%. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with NS group; ▲P<0.05 compared with NI/R group; #P<0.05 compared with DS group. Abbreviations: Ctrl, control; DM, diabetes mellitus; HE, Hematoxylin and Eosin.
Figure 1 A diabetic model of adult male SD rats was induced using STZ All rats were subjected to sham surgery or bilateral renal I/R injury. (A) Renal Hematoxylin and Eosin staining. Magnification: 200×. The lower panels are the magnified images of the boxed areas in the upper panels. (B) TUNEL staining. Magnification: 400×. (C) Histopathological scoring. (D) TUNEL assay apoptosis%. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with NS group; ▲P<0.05 compared with NI/R group; #P<0.05 compared with DS group. Abbreviations: Ctrl, control; DM, diabetes mellitus; HE, Hematoxylin and Eosin.CC BY · PubMed Central
Figure 2 Serum BUN, creatinine, and renal tissues SOD and MDA levels in the different treatment groups (A) BUN. (B) Scr. (C) Kidney SOD contents. (D) MDA activity. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with NS group; ▲P<0.05 compared with NI/R group; #P<0.05 compared with DS group. Abbreviations: Ctrl, control; DM, diabetes mellitus.
Figure 2 Serum BUN, creatinine, and renal tissues SOD and MDA levels in the different treatment groups (A) BUN. (B) Scr. (C) Kidney SOD contents. (D) MDA activity. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with NS group; ▲P<0.05 compared with NI/R group; #P<0.05 compared with DS group. Abbreviations: Ctrl, control; DM, diabetes mellitus.CC BY · PubMed Central
Figure 3 Expression of SIRT1, Nrf2, and HO-1 in renal tissues by Western blot analysis (A) Western blotting showed protein levels of SIRT1, Nrf2, and HO-1. (B–D) Quantitation of Western blot data from (A). Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with NS group; ▲P<0.05 compared with NI/R group; #P<0.05 compared with DS group. Abbreviations: Ctrl, control; DM, diabetes mellitus.
Figure 3 Expression of SIRT1, Nrf2, and HO-1 in renal tissues by Western blot analysis (A) Western blotting showed protein levels of SIRT1, Nrf2, and HO-1. (B–D) Quantitation of Western blot data from (A). Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with NS group; ▲P<0.05 compared with NI/R group; #P<0.05 compared with DS group. Abbreviations: Ctrl, control; DM, diabetes mellitus.CC BY · PubMed Central
Figure 4 Melatonin pre-treatment markedly ameliorated the histology score and apoptosis after bilateral renal I/R injury in diabetic rats (A) Renal HE staining. Magnification: 200×. The lower panels are the magnified images of the boxed areas in the upper panels. (B) TUNEL staining. Magnification: 400×. (C) Histopathological scoring. (D) TUNEL assay apoptosis%. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with DS group; ▲P<0.05 compared with DI/R+melatonin group. Abbreviation: HE, Hematoxylin and Eosin.
Figure 4 Melatonin pre-treatment markedly ameliorated the histology score and apoptosis after bilateral renal I/R injury in diabetic rats (A) Renal HE staining. Magnification: 200×. The lower panels are the magnified images of the boxed areas in the upper panels. (B) TUNEL staining. Magnification: 400×. (C) Histopathological scoring. (D) TUNEL assay apoptosis%. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with DS group; ▲P<0.05 compared with DI/R+melatonin group. Abbreviation: HE, Hematoxylin and Eosin.CC BY · PubMed Central
Figure 5 Melatonin pre-treatment attenuates kidney dysfunction and oxidative stress after I/R injury in diabetic rats (A) BUN. (B) Scr. (C) Kidney SOD contents. (D) MDA activity. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with DS group; ▲P<0.05 compared with DI/R+melatonin group.
Figure 5 Melatonin pre-treatment attenuates kidney dysfunction and oxidative stress after I/R injury in diabetic rats (A) BUN. (B) Scr. (C) Kidney SOD contents. (D) MDA activity. Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with DS group; ▲P<0.05 compared with DI/R+melatonin group.CC BY · PubMed Central
Figure 6 Melatonin pre-treatment up-regulates SIRT1, Nrf2, and HO-1 expression after kidney I/R injury in diabetic rats (A) Western blotting showed protein levels of SIRT1, Nrf2, and HO-1. (B–D) Quantitation of Western blot data from (A). Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with DS group; ▲P<0.05 compared with DI/R+melatonin group.
Figure 6 Melatonin pre-treatment up-regulates SIRT1, Nrf2, and HO-1 expression after kidney I/R injury in diabetic rats (A) Western blotting showed protein levels of SIRT1, Nrf2, and HO-1. (B–D) Quantitation of Western blot data from (A). Data are presented as the mean ± S.E.M. (n=6 per group). ★P<0.05 compared with DS group; ▲P<0.05 compared with DI/R+melatonin group.CC BY · PubMed Central

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Research works printed but not linked: 3

  1. Bao, 2018, Kidney disease models: tools to identify mechanisms and potential therapeutic targets, Zool. Res., 39, 72
  2. Bai, 2016, Melatonin prevents acute kidney injury in severely burned rats via the activation of SIRT1, Sci. Rep., 6, 32199, 10.1038/srep32199 · DOI
  3. Hadj, 2015, Melatonin modulates endoplasmic reticulum stress and Akt/GSK3-beta signaling pathway in a rat model of renal warm ischemia reperfusion, Anal. Cell Pathol. (Amst.), 2015, 635172

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Metadata

Authors
Shi, S., Lei, S., Tang, C., Wang, K., & Xia, Z.
Affiliations
  • Renmin Hospital of Wuhan University (CN)
  • University of Science and Technology of China (CN)
Corresponding author
Xia, Zhongyuan
ORCID
Venue
Bioscience Reports
Publisher
Portland Press Ltd.
Published
2019-01
Volume
39
Issue
1
ISSN
  • 0144-8463 (ISSN-L)
  • 1573-4935
DOI
10.1042/bsr20181614
PMC
PMC6331666
OpenAlex
W2906001979
Cited by
135
References
71
Citations by year
2026: 9 · 2025: 18 · 2024: 15 · 2023: 18 · 2022: 28 · 2021: 19 · 2020: 21 · 2019: 7
FWCI
9.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Bioscience Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (WK9110000044, 81801175, 81671891)
  • China Scholarship Council (201706270155)
  • University of Science and Technology of China
  • Fundamental Research Funds for the Central Universities (81801175, WK9110000044)
  • School of Life Sciences and Biotechnology Division of Life Sciences, Korea University
Topics
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
melatonin, diabetic kidney, SIRT1, Nrf2, heme oxygenase-1, oxidative stress, apoptosis, streptozotocin-induced diabetes, EX527, SIRT1 inhibition, renal protection
MeSH terms
Animals, Carbazoles, Diabetes Mellitus, Experimental, Humans, Kidney, Melatonin, Signal Transduction, Reperfusion Injury, Apoptosis, Oxidative Stress, NF-E2-Related Factor 2, Rats, Heme Oxygenase-1, Sirtuin 1, Acute Kidney Injury

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