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. 2022 Mar;80(1):191-202.
doi: 10.1007/s12013-022-01064-6. Epub 2022 Feb 14.

The Protective Role of Celastrol in Renal Ischemia-Reperfusion Injury by Activating Nrf2/HO-1, PI3K/AKT Signaling Pathways, Modulating NF-κb Signaling Pathways, and Inhibiting ERK Phosphorylation

Nancy S Younis  1 , Amal M H Ghanim  2
Affiliations

The Protective Role of Celastrol in Renal Ischemia-Reperfusion Injury by Activating Nrf2/HO-1, PI3K/AKT Signaling Pathways, Modulating NF-κb Signaling Pathways, and Inhibiting ERK Phosphorylation

Nancy S Younis et al. Cell Biochem Biophys. 2022 Mar.

Abstract

Celastrol, a natural triterpenoid derived from Tripterygium wilfordii, possesses numerous biological effects. We investigated celastrol's antioxidant potential through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) and its effect on phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling, nuclear factor-kappa B (NF-κB) pathways, and extracellular signal-regulated kinase (ERK) activation in kidney ischemia-reperfusion injury (IRI) rat model. Rats were given celastrol 2 mg/kg orally for 1 week before subjection to renal ischemia-reperfusion surgery. Kidney functions, renal MDA, and reduced glutathione were determined; also, renal levels of ERK1/2, HO-1, PI3K, IL-6, TNF-α, IκBα, NF-κB/p65, and cleaved caspase-3 were measured. In addition, gene expression of kidney injury molecule-1 (KIM-1), Nrf-2, and AKT were determined. Celastrol pretreatment attenuated oxidative stress and increased Nrf2 gene expression and HO-1 level. Also, it activated the PI3K/AKT signaling pathway and decreased the p-ERK:t- ERK ratio and NFκBp65 level, with a remarkable decrease in inflammatory cytokines and cleaved caspase-3 levels compared with those in renal IRI rats. Conclusively, celastrol showed a reno-protective potential against renal IRI by suppressing oxidative stress through enhancing the Nrf2/HO-1 pathway, augmenting cell survival PI3K/AKT signaling pathways, and reducing inflammation by inhibiting NF-κB activation.

Keywords: Celastrol; ERK phosphorylation; Nrf2/HO-1; PI3K/AKT; Renal Ischemia-Reperfusion.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Chemical structure of celastrol
Fig. 2
Fig. 2
Effect of celastrol treatment (2 mg/kg; PO) on gene expression of a KIM-1, b Nrf2, and c HO-1 levels in renal IRI rats. All results were expressed as mean ± SD; n = 6 in each. KIM-1 kidney injury molecule-1, Nrf2 nuclear factor erythroid 2-related factor 2, HO-1 hemoxygenase-1, IRI ischemia-reperfusion injury. +++P < 0.001, +P < 0.05 compared with the sham group, ***P < 0.001 compared with the renal IRI group
Fig. 3
Fig. 3
Effect of celastrol treatment (2 mg/kg; PO) on the level of a PI3K and gene expression of b AKT in renal IRI rats. All results were expressed as mean ± SD; n = 6 in each. PI3K phosphoinositide 3-kinase, AKT protein kinase B, IRI ischemia-reperfusion injury. +++P < 0.001, ++P < 0.01 compared with the sham group, ***P < 0.001 compared with the renal IRI group
Fig. 4
Fig. 4
Effect of celastrol treatment (2 mg/kg; PO) on a P-ERK1/2:t-ERK1/2 ratio, levels of b NF-kBP65 and c IκB-α in renal IRI rats. All results were expressed as mean ± SD; n = 6 each. ERK extracellular signal-regulated kinase, NF-kBP65 nuclear transcription factor-kappa B P65, IκB-α inhibitor of kappa B alpha, IRI ischemia-reperfusion injury. +++P < 0.001 and ++P < 0.01 compared with the sham group, ***P < 0.001 and *P < 0.05 compared with the renal IRI group
Fig. 5
Fig. 5
Effect of celastrol treatment (2 mg/kg; PO) on levels of a IL-6, b TNFα, and c cleaved caspase-3 in renal IRI rats. All results were expressed as mean ± SD; n = 6 each. IL-6 interleukin-6, TNF α tumor necrosis factor-alpha, IRI ischemia-reperfusion injury. +++P < 0.001, +P < 0.05 compared with the sham group, ***P < 0.001 compared with the renal IRI group
Fig. 6
Fig. 6
Effect of celastrol treatment (2 mg/kg; PO) on H&E-stained kidney sections of renal IRI rats. Representative microscopic pictures of H&E-stained kidney sections showed well-organized glomeruli (black arrows) and normal tubules (yellow arrow) in sham-operated rats (a). Kidney sections from sham-operated rats treated with cela showed mild disorganization of the glomeruli with moderate congestion of its capillaries (black arrows), and the tubules are within normal (yellow arrows) (b). In kidney sections of renal IRI rats, most glomeruli were collapsed with focal necrosis (black arrows), the tubules showed marked necrosis with loss of the histologic details (yellow arrows), and the stroma showed many foci of interstitial hemorrhage (green arrows) (c, d). Kidney sections from renal IRI + cela treated rats showed Hyperplastic glomeruli with mild congestion (black arrows), some tubules showed sloughed epithelial cells (yellow arrows), others showed hyaline casts (green arrows), regenerated tubules with active vesicular nuclei are detected between damaged tubules (crooked arrows) (e) (H&E ×200). H&E hematoxylin and eosin, cela celastrol, IRI ischemia-reperfusion injury
Fig. 7
Fig. 7
Effect of celastrol treatment (2 mg/kg; PO) on PAS-stained kidney sections of renal IRI rats. Representative microscopic pictures of PAS-stained kidney sections showed well-organized glomeruli with good staining of the capillary’s basement membrane with PAS stain (black arrow). In addition, the tubules showed well-demarcated outer basement membrane and inner brush border (yellow arrows) in sham-operated rats (a). Kidney sections from sham-operated rats treated with cela showed PAS staining of the glomerular capillaries’ basement membrane (black arrows) with prominent PAS-positive brush border (yellow arrows) (b). kidney sections of renal IRI rats showed wrinkling and thickening of capillary basement membranes and collapse of the capillary lumen (black arrows) with significant tubular necrosis and cast formation (green arrows) (c). Kidney sections from renal IRI + cela treated rats showed hyperplastic glomeruli with the moderate demarcation of its capillaries’ basement membrane (black arrow). Damaged tubules lost their basement membrane and inner brush border (yellow arrows). Regenerated tubules with the restoration of PAS staining of the basement membrane and brush border (green arrows) (d, e) (PAS stain ×400). PAS Periodic acid–Schiff, cela celastrol, IRI ischemia-reperfusion injury
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