the control group; ## 0

the control group; ## 0.01 vs. BUN and serum creatinine (72?h of CDDP). The lost bodyweight, and the increase of kidney index, BUN and creatinine were higher in Nrf2?/? KI mice than those in WT mice (Figures 1BCE). In the group of CDDP, macroscopic kidneys exhibited whitening, which confirmed that Nrf2?/? mice were susceptible to toxin insult (Physique 1F). Consistently, the histological assessment of the kidneys indicated a significantly worse tubular injury in the Nrf2?/? mice than it in the WT mice, including severe dilation of the proximal tubules, cast formation, and Rabbit Polyclonal to Tip60 (phospho-Ser90) massive detachment and necrosis of the tubular epithelium (Figures 1G,H). Open in a separate window Physique 1 Nrf2?/? mice are more susceptible to CDDP-induced AKI. (A) An acute kidney injury model was induced 3?days after i.p. injection of CDDP (10, 20?mg/kg). WT mice and Nrf2 knockout (KO) mice treated with CDDP (10, 20?mg/kg) are shown. (B) Body weight and (C) Kidney/body excess weight ratio. (D,E) BUN and serum creatinine were measured. (F) macroscopic kidney and (G) hematoxylin and eosin (H&E). (H) Tubular injury scores for kidney damage. * 0.05, ** 0.01. Daph Effectively Ameliorates Cisplatin-Induced AKI in Wild-Type Mice Our previous studies found that Daph, as the main Nrf2 activator, exert antioxidant activity by regulating the Nrf2/ARE pathway (Lv et al., 2017; Lv et al., 2018). We utilized it to investigate its protective effects on CDDP-induced nephrotoxicity. After fasting for 12?h, the mice received a single dose of CDDP alone (20?mg/kg) to induce AKI or in combination with the ip administration of Daph for three times (Physique 2B). As indicated in Figures 2CCI, the administration of Daph significantly reversed the CDDP-induced loss of body weight and the high levels of kidney index, BUN and serum creatinine and tubular necrosis. Open in a separate window Physique 2 Daph protects against CDDP-induced AKI in WT mice. (A) The molecular structure of Daph. (B) Schematic routine for CDDP alone and combined with Daph or NAC treatments = 5 for all those test groups. * 0.05, ** 0.01. Daph Protects Isoprenaline HCl Wild-Type Mice From Oxidative and Inflammatory Damage Induced by Cisplatin As oxidative damage is crucial in CDDP-induced AKI, we investigated whether Daph pretreatment could reduce kidney damage by inhibiting oxidative stress. We Isoprenaline HCl detected SOD, GSH, MPO and MDA levels related to oxidation. As indicated in Figures 3ACD, Daph treatment significantly increased SOD and GSH levels, decreased MPO and MDA levels. Subsequently, we examined changes in the expression levels of Daph on oxidative protein. As offered in Physique 3E, Daph treatment amazingly suppressed the expression levels of NOX4, and increasing the expression levels of SIRT1, SIRT6, Nrf2, HO-1 and NQO1 compared with the CDDP only group. These data show that the protective effects of Daph on CDDP-induced kidney injury by enhancing SIRT1, SIRT6 and Nrf2 and its regulated antioxidant enzymes. Open in a separate windows Physique 3 Daph inhibits oxidative stress and inflammation in WT mice. (ACD) MPO, MDA, SOD and GSH levels in AKI mice. (E) Western blots analysis showing the expression levels of SIRT1, SIRT6, total Nrf2, nuclear Nrf2, cytoplasmic Nrf2, HO-1, NQO1 and NOX4 in the kidneys from WT mice. (F) Western blots analysis showing the expression levels of p-JNK, JNK, p-p38, p38, (p)-ERK1/2, ERK1/2, HMGB1 and NF-B in the kidneys from WT mice. Data are offered as the mean SEM, n = 5 for all those test groups. * 0.05 and ** 0.01 vs. the control group; # 0.05 and ## Isoprenaline HCl 0.01 vs. the CDDP group. As indicated in Physique 3F, CDDP obviously enhancing the expression levels of NF-B and HMGB1 and phosphorylation of JNK, ERK, and P38. But, treatment with Daph obviously suppress this phenomenon. In conclusion, increasing evidence demonstrates that this Nrf2-mediated signaling pathway is crucial for the suppression of oxidative stress and.

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