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. 2023 Jul 20;24(1):22.
doi: 10.1186/s12860-023-00485-2.

Knockdown of ELF4 aggravates renal injury in ischemia/reperfusion mice through promotion of pyroptosis, inflammation, oxidative stress, and endoplasmic reticulum stress

Li Li  1 , Shunying Wang  2 , Wenming Wang  2
Affiliations

Knockdown of ELF4 aggravates renal injury in ischemia/reperfusion mice through promotion of pyroptosis, inflammation, oxidative stress, and endoplasmic reticulum stress

Li Li et al. BMC Mol Cell Biol. .

Abstract

Background: Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Dysfunction of E74-like ETS transcription factor 4 (ELF4) leads to inflammation. This research intended to look into the function and mechanisms of ELF4 in I/R and oxygen-glucose deprivation/reperfusion (OGD/R) model.

Results: In I/R and OGD/R model, ELF4 expression was downregulated. ELF4 knockout aggravated I/R-induced kidney injury, oxidative stress (OS), endoplasmic reticulum stress (ERS), apoptosis, inflammation, and pyroptosis in mice. In HK-2 cells treated with OGD/R, suppression of ELF4 expression inhibited cell proliferation and promoted cell apoptosis, OS, ERS, inflammation, and pyroptosis. Moreover, ELF4 overexpression led to the opposite results.

Conclusion: ELF4 deficiency aggravated I/R induced AKI, which was involved in apoptosis, OS, ERS, inflammation, and pyroptosis. Targeting ELF4 may be a promising new therapeutic strategy for preventing inflammation after IR-AKI.

Keywords: Acute kidney injury; ELF4; Inflammation; Oxidative stress; Pyroptosis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
In kidney tissues of I/R mice and cells of OGD/R, ELF4 expression was decreased. A ELF4 mRNA expression was detected by way of qRT-PCR in kidney tissues of sham and I/R mice. ELF4 protein expression in kidney tissues of sham and I/R mice was surveyed using western blot (B) and immunohistochemistry (C). D In kidney tissues of WT and ELF4−/− mice, ELF4 protein change was ascertained using western blot. E ELF4 mRNA expression was surveyed by way of qRT-PCR in HK-2 cells. F In HK-2 cells, western blot was applied to survey ELF4 protein expression. G ELF4 mRNA expression was surveyed by way of qRT-PCR in HK-2 cells. H In HK-2 cells, ELF4 protein expression was checked by way of western blot. Mouse n = 5. Cell n = 3. * p < 0.05 vs sham, WT, or control group; # p < 0.05 vs OGD/R group
Fig. 2
Fig. 2
In I/R mice, ELF4 deficiency aggravated kidney injury. Serum Cr (A) and BUN levels (B) in WT and ELF4−/− mice. C In WT and ELF4−/− mice, the renal histological injury was estimated by way of H&E staining. D KIM-1 protein change was ascertained in kidney tissues of WT and ELF4−/− mice using western blot. Mouse n = 5. * p < 0.05 WT sham group, # p < 0.05 ELF4−/− sham or WT I/R group
Fig. 3
Fig. 3
ELF4 deficiency aggravated apoptosis. A In WT and ELF4-/- mice, TUNEL staining was applied to survey renal cell apoptosis. B Bax and Bcl-2 protein levels were detected by way of western blot in kidney tissues of WT and ELF4-/- mice. C HK-2 cell viability was ascertained by way of CCK-8 assay. D Flow cytometry was carried out to assess cell apoptosis in HK-2 cells. Mouse n = 5. Cell n = 3. * p < 0.05 WT sham or control group, # p < 0.05 ELF4−/− sham, WT I/R, or OGD/R group
Fig. 4
Fig. 4
ELF4 deficiency aggravated OS and ERS. Serum SOD (A), CAT (B), and GSH-PX (C) levels in WT and ELF4−/− mice. D In kidney tissues of WT and ELF4−/− mice, Nrf2, HO-1, and NQO-1 protein levels were surveyed by way of western blot. E GRP78, CHOP, and caspase-12 protein levels were detected by way of western blot in kidney tissues of WT and ELF4−/− mice. F Flow cytometry was carried out to assess ROS levels in HK-2 cells. The levels of OS related proteins (Nrf2, HO-1, and NQO-1; G), ER stress related proteins (GRP78, CHOP, and caspase-12; H) were surveyed using western blot in HK-2 cells. Mouse n = 5. Cell n = 3. * p < 0.05 WT sham or control group, # p < 0.05 ELF4−/− sham, WT I/R, or OGD/R group
Fig. 5
Fig. 5
ELF4 deficiency aggravated inflammation and pyroptosis. A In kidney tissues of WT and ELF4−/− mice, IL-6, TNF-α, IL-18, and IL-1β protein levels were detected by way of western blot. B GSDMD, N-GSDMD, and caspase-11 protein levels were surveyed in kidney tissues of WT and ELF4−/− mice using western blot. The levels of inflammatory cytokines (IL-6, TNF-α, IL-18, and IL-1β; C), and pyroptosis-related proteins (GSDMD, N-GSDMD, and caspase-11; D) were detected using western blot in HK-2 cells. Mouse n = 5. Cell n = 3. * p < 0.05 WT sham or control group, # p < 0.05 ELF4−/− sham, WT I/R, or OGD/R group
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