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. 2016 Oct;12(4):2009-2014.
doi: 10.3892/etm.2016.3603. Epub 2016 Aug 22.

Osthole decreases renal ischemia-reperfusion injury by suppressing JAK2/STAT3 signaling activation

Lin-Na Luo  1 , De Qiong Xie  1 , Xiao Gang Zhang  2 , Rong Jiang  3
Affiliations

Osthole decreases renal ischemia-reperfusion injury by suppressing JAK2/STAT3 signaling activation

Lin-Na Luo et al. Exp Ther Med. 2016 Oct.

Abstract

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. The pathogenetic mechanisms underlying renal I/R injury involve inflammation, oxidative stress and apoptosis. Osthole is a coumarin derivative that exhibits potential anti-inflammatory activity. The aim of the present study was to investigate the effect of osthole in renal I/R injury and its underlying mechanism. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 24 h reperfusion with the contralateral nephrectomy. A total of 70 rats were randomly assigned to seven groups (n=10 per group): Sham; IRI; and osthole (0, 5, 10, 20 and 40 mg/kg) groups. Rats were administered intraperitoneally with osthole 45 min prior to renal ischemia. Serum and renal tissue were harvested 24 h after reperfusion. Renal function and histological changes were assessed. In addition, the mRNA and protein expression of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8) and interleukin-6 (IL-6) in renal tissue and serum were evaluated using quantitative polymerase chain reaction and ELISA assays, respectively. The protein expression levels of p65, p-p65, janus kinase 2 (JAK2), p-JAK2, signal transducer and activator of transcription 3 (STAT3) and p-STAT3 were measured using western blot analysis. The results indicate that osthole pretreatment was able to significantly attenuate the renal dysfunction in a dose-dependent manner, histological changes and the expression of TNF-α, IL-8, IL-6, p-JAK2, p-STAT3 and p-p65 induced by renal I/R injury. However, neither osthole or I/R injury affected the expression p65, JAK2 and STAT3. Osthole pretreatment is able to reduce renal I/R injury by abrogating inflammation and the mechanism is partially involved in suppressing JAK2/STAT3 activation. Thus, osthole may be a novel practical strategy for the mitigation of renal I/R injury.

Keywords: inflammation; ischemia reperfusion injury; janus kinase 2/signal transducer and activator of transcription 3; osthole; renal.

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Figures

Figure 1.
Figure 1.
Effects of osthole pretreatment on alterations of renal function following renal ischemia/reperfusion (I/R)-induced injury. (A) Serum Cr and (B) BUN levels were evaluated to assess the renoprotective effect of against renal I/R osthole pretreatment injury in the sham, IRI and osthole groups. Data are presented as the mean ± standard error of the mean (n=10). ***P<0.001 vs. sham; #P<0.005 vs. osthole. Cr, creatinine; IRI, ischemia/reperfusion vehicle group; BUN, blood urea nitrogen.
Figure 2.
Figure 2.
Hematoxylin and eosin staining for histopathological changes: Effects of osthole pretreatment on ischemia/reperfusion (I/R)-induced renal injury. (A) The Sham group shows no histopathological change 24 h after I/R injury (Sham; magnification, ×200). (B) The I/R injury (IRI) group shows widespread degeneration of the tubular architecture, tubular dilation, tubular cell swelling, cellular vacuolization, tubular cell necrosis and inflammatory cell infiltration 24 h after IRI (magnification, ×200). (C) The osthole group shows little degeneration of the tubular architecture, tubular dilation, tubular cell swelling, cellular vacuolization, tubular cell necrosis and inflammatory cell infiltration 24 h after IRI (magnification, ×200). (D) Semi-quantitative assessment of the histological lesions based on renal histopathological changes. Data are presented as the mean ± standard error of the mean (n=10). ***P<0.001, vs. Sham; ###P<0.001, vs. osthole.
Figure 3.
Figure 3.
Effects of osthole pretreatment on the expression of proinflammatory cytokines after renal ischemia/reperfusion injury. Quantitative polymerase chain reaction was used to assess the expression of inflammatory cytokines in the kidney. The mRNA expression levels for (A) TNF-α, (B) IL-6 and (C) IL-8 after IRI were selectively evaluated. Data are presented as the mean ± standard error of the mean (n=10). ***P<0.001 vs. sham; ##P<0.001, #P<0.05 vs. osthole. TNF-α, tumor necrosis factor-α; IRI, ischemia/reperfusion vehicle group; IL-6, interleukin-6; IL-8, interleukin-8
Figure 4.
Figure 4.
Effects of osthole pretreatment on the secretion of proinflammatory cytokine after renal ischemia/reperfusion injury. ELISA was employed to assess the expression of proinflammatory cytokine in the serum. The expression levels of (A) TNF-α, (B) IL-6 and (C) IL-8 after IRI were selectively detected. Data are presented as the mean ± standard error of the mean (n=10). ***P<0.001 vs. sham; ##P<0.01, #P<0.05 vs. osthole. TNF-α, tumor necrosis factor-α; IRI, ischemia/reperfusion vehicle group; IL-6, interleukin-6; IL-8, interleukin-8
Figure 5.
Figure 5.
Effects of osthole pretreatment on the expression of p65 following renal ischemia/reperfusion injury. Western blot analysis was employed to evaluate the protein expression of p65 and p-p65. (A) Representative western blot analysis of p65. (B) Semi-quantitative analysis of 10 animals studied in each group. Relative quantities of p-p65 and p65 in each group of rats were normalized against β-actin and presented as a ratio between p-p65 and p65. ***P<0.001 vs. sham; #P<0.05 vs. IRI. IRI, ischemia/reperfusion vehicle group.
Figure 6.
Figure 6.
Effects of osthole pretreatment on the JAK2/STAT3 signaling after renal ischemia/reperfusion injury. Western blot analysis was employed to semi-quantitatively analyze the protein expression levels of JAK2, p-JAK2, STAT3 and p-STATA3. (A) Representative result for western blot analysis of JAK2. (B) Relative quantities of p-JAK2 and JAK2 in each group of rats were normalized against β-actin and presented as a ratio between p-JAK2 and JAK2. **P<0.01 vs. sham; #P<0.05 vs. IRI. (C) Representative result for western blot analysis of STAT3. (D) Relative quantities of STAT3 and p-STAT3 in each group of rats were normalized against β-actin and presented as a ratio between p-STAT3 and STAT3. *P<0.05 vs. sham; #P<0.05 vs. IRI.
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