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. 2022 Aug 13;11(8):1568.
doi: 10.3390/antiox11081568.

Renal Ischemia/Reperfusion Mitigation via Geraniol: The Role of Nrf-2/HO-1/NQO-1 and TLR2,4/MYD88/NFκB Pathway

Maged E Mohamed  1   2 , Mohammad A Elmorsy  3   4 , Nancy S Younis  1   2
Affiliations

Renal Ischemia/Reperfusion Mitigation via Geraniol: The Role of Nrf-2/HO-1/NQO-1 and TLR2,4/MYD88/NFκB Pathway

Maged E Mohamed et al. Antioxidants (Basel). .

Abstract

Background: Renal ischemia/reperfusion injury is a clinically recurrent event during kidney transplantation. Geraniol is a natural monoterpene essential oil component. This study aimed to inspect geraniol's reno-protective actions against renal I/R injury with further analysis of embedded mechanisms of action through scrutinizing the Nrf-2/HO-1/NQO-1 and TLR2,4/MYD88/NFκB signaling pathways.

Methods: Wistar male rats were randomized into five groups: Sham, Sham + geraniol, Renal I/R, and two Renal I/R + geraniol groups representing two doses of geraniol (100 and 200 mg/kg) for 14 days before the renal I/R. Renal I/R was surgically induced by occluding both left and right renal pedicles for 45 min, followed by reperfusion for 24 h. A docking study was performed to anticipate the expected affinity of geraniol towards three protein _targets: hTLR4/MD2, hTLR2, and hNrf2/Keap1.

Results: Renal I/R rats experienced severely compromised renal functions, histological alteration, oxidative stress status, escalated Nrf-2/HO-1/NQO-1, and amplified TLR2,4/MYD88/NFκB. Geraniol administration ameliorated renal function, alleviated histological changes, and enhanced Nrf-2/HO-1/NQO-1 with a subsequent intensification of antioxidant enzyme activities. Geraniol declined TLR2,4/MYD88/NFκB with subsequent TNF-α, IFN-γ, MCP-1 drop, Bax, caspase-3, and caspase-9 reduction IL-10 and Bcl-2 augmentation. Geraniol exhibited good fitting in the binding sites of the three in silico examined _targets.

Conclusions: Geraniol might protect against renal I/R via the inhibition of the TLR2,4/MYD88/NFκB pathway, mediating anti-inflammation and activation of the Nrf2 pathway, intervening in antioxidative activities.

Keywords: anti-inflammatory; antioxidant; essential oil; geraniol; renal ischemia/reperfusion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Geraniol chemical structure. (b) Pharmacokinetics and bioavailability radar graph of geraniol. The data were calculated in silico using the SwissADME web tool [20]. The pink area in the radar graph represents the optimal range for each particular property for studied compounds (LIPO = lipophilicity as XLOGP3; SIZE = size as molecular weight; POLAR = polarity as TPSA (topological polar surface area); INSOLU = insolubility in water by log S scale; INSATU = in saturation as per fraction of carbons in the sp3 hybridization and FLEX = flexibility as per rotatable bonds).
Figure 2
Figure 2
The influences of geraniol (100 and 200 mg/kg) administration for 14 days prior to renal ischemia/perfusion (I/R) induced injury on the renal function assessment, including (a) creatinine, (b) BUN, (c) uric acid, (d) Kim-1, and (e) LDL. All values are expressed as mean  ±  SD. ¥ indicates statistically significant from the sham group, ₳ indicates statistically significant from the renal I/R group, and φ indicates statistically significant from renal I/R + geraniol 100 mg/kg group (p < 0.05) using one-way ANOVA followed by Tukey’s post hoc test.
Figure 3
Figure 3
The influences of geraniol (100 and 200 mg/kg) administration for 14 days prior to renal ischemia/perfusion (I/R) induced injury on the antioxidant status, including (a) MDA, (b) GPx, (c) GSH content, (d) SOD, and (e) CAT. All values are expressed as mean  ±  SD. ¥ indicates statistically significant from the sham group, ₳ indicates statistically significant from the renal I/R group, and φ indicates statistically significant from renal I/R + geraniol 100 mg/kg group (p < 0.05) using one-way ANOVA followed by Tukey’s post hoc test.
Figure 4
Figure 4
Three-dimensional binding mode of geraniol docking study (a) Geraniol (orange) inside the binding site of hTLR4/MD2 (hTLR4 in silver and MD2 in gold), (b) Geraniol (orange) inside the binding site of hTLR2, and (c) Geraniol (orange) inside the binding site of Keap1 protein.
Figure 4
Figure 4
Three-dimensional binding mode of geraniol docking study (a) Geraniol (orange) inside the binding site of hTLR4/MD2 (hTLR4 in silver and MD2 in gold), (b) Geraniol (orange) inside the binding site of hTLR2, and (c) Geraniol (orange) inside the binding site of Keap1 protein.
Figure 5
Figure 5
The influences of geraniol (100 and 200 mg/kg) administration for 14 days prior to renal ischemia/perfusion (I/R) induced injury on the renal gene (mRNA) expression of (a) Nrf2, (b) HO-1, (c) NQO-1, and protein expression of (d) nuclear Nrf2, (e) HO-1, and (f) NQO-1. All values are expressed as mean  ±  SD. ¥ indicates statistically significant from the sham group, ₳ indicates statistically significant from the renal I/R group, and φ indicates statistically significant from renal I/R + geraniol 100 mg/kg group (p < 0.05) using one-way ANOVA followed by Tukey’s posthoc test.
Figure 6
Figure 6
The influences of geraniol (100 and 200 mg/kg) administration for 14 days prior to renal ischemia/perfusion (I/R) induced injury on the renal gene (mRNA) expression of (a) TLR2, (b) TLR4, (c) MYD88, and (d) NFκB. All values are expressed as mean  ±  SD. ¥ indicates statistically significant from the sham group, ₳ indicates statistically significant from the renal I/R group, and φ indicates statistically significant from renal I/R + geraniol 100 mg/kg group (p < 0.05) using one-way ANOVA followed by Tukey’s post hoc test.
Figure 7
Figure 7
The influences of geraniol (100 and 200 mg/kg) administration for 14 days prior to renal ischemia/perfusion (I/R) induced injury on the renal inflammatory mediators (a) TNF-α, (b) IFN-γ, (c) MCP-1, and (d) IL-10, and on apoptosis including gene (mRNA) expression of (e) Bax, (f) Bcl-2 and (g) Caspase 3, and (h) Caspase 9. All values are expressed as mean  ±  SD. ¥ indicates statistically significant from the sham group, ₳ indicates statistically significant from the renal I/R group, and φ indicates statistically significant from renal I/R + geraniol 100 mg/kg group (p < 0.05) using one-way ANOVA followed by Tukey’s post hoc test.
Figure 8
Figure 8
Geraniol’s histopathological effects in renal I/R induced injury. Black arrows show collapsed glomeruli with focal necrosis, blue arrows indicate tubular hypertrophy, green arrows indicate many foci of interstitial hemorrhage, and yellow arrows display sloughed epithelial cells.
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