The Emerging Evidence for a Protective Role of Fucoidan from Laminaria japonica in Chronic Kidney Disease-Triggered Cognitive Dysfunction

Abstract

This study aimed to explore the mechanism of fucoidan in chronic kidney disease (CKD)-triggered cognitive dysfunction. The adenine-induced ICR strain CKD mice model was applied, and RNA-Seq was performed for differential gene analysis between aged-CKD and normal mice. As a result, fucoidan (100 and 200 mg kg^-1) significantly reversed adenine-induced high expression of urea, uric acid in urine, and creatinine in serum, as well as the novel object recognition memory and spatial memory deficits. RNA sequencing analysis indicated that oxidative and inflammatory signaling were involved in adenine-induced kidney injury and cognitive dysfunction; furthermore, fucoidan inhibited oxidative stress via GSK3β-Nrf2-HO-1 signaling and ameliorated inflammatory response through regulation of microglia/macrophage polarization in the kidney and hippocampus of CKD mice. Additionally, we clarified six hallmarks in the hippocampus and four in the kidney, which were correlated with CKD-triggered cognitive dysfunction. This study provides a theoretical basis for the application of fucoidan in the treatment of CKD-triggered memory deficits.

Keywords: GSK3β-Nrf2-HO-1 signaling; chronic kidney disease; cognitive dysfunction; fucoidan; microglial polarization; neuroinflammation; oxidative stress.

Figure 1

Effects of fucoidan on body and renal indexes in adenine-induced CKD mice. ICR mice (male, 8-week-old) were orally co-administered with fucoidan (Fuc), losartan (Los) or vehicle (saline), and adenine (0.25% contained diets) for 33 days. (A) Body weight and kidney index (kidney weight/body weight) among five groups. (B) Body weight variable rate (the increased body weight ratio between last and first drug treatment). (C) Total distance moved (within 8 min) in the open field test. The expression levels of uric acid (D), urea (E), and creatinine (F) were determined by ELISA kits. The data are expressed as mean ± SEM (n = 10). * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle group (Veh), one-way ANOVA post hoc Dunnett’s test.

Figure 2

Effects of fucoidan on memory function in adenine-induced CKD mice. (A) Object recognition test (ORT). The preferential indexes for the training and test sessions are shown. p = 0.017, drug × time interaction was analyzed using repeated measures two-way ANOVA, F(4, 28) = 3.64. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle-treated CKD mice, post hoc Dunnett’s test. (B) Object location test (OLT). The preferential indexes for the training and test sessions are shown. p = 0.0998, drug × time interaction was analyzed using repeated measures two-way ANOVA, F(4, 56) = 2.05. * p < 0.05, ** p < 0.01 vs. vehicle-treated CKD mice, post hoc Dunnett’s test. (C) The step-through latency entering the darkroom in passive avoidance memory test. p = 0.288, drug × time interaction was analyzed using repeated measures two-way ANOVA, F(4, 56) = 1.28. ** p < 0.01 vs. vehicle-treated CKD mice, post hoc Dunnett’s test. (D) The number of errors into the darkroom were measured. p = 0.482, drug × time interaction was analyzed using repeated measures two-way ANOVA, F(4, 44) = 0.88. ** p < 0.01, *** p < 0.001 vs. vehicle-treated CKD mice, post hoc Dunnett’s test. The data are expressed as mean ± SEM (n = 8).

Figure 3

Column chart of GO annotation in the brain and kidney of CKD mice. GO analysis in the kidney (A) and brain (B) between aged-CKD and young mice was performed. The data are expressed as mean ± SEM (n = 3).

Figure 4

Bubble diagram of GO enrichment analysis of differential genes. GO enrichment analysis in the brain (A) and kidney (B) between aged-CKD and young mice was performed. The data are expressed as mean ± SEM (n = 3).

Figure 5

Effects of fucoidan on oxidative indexes in adenine-induced CKD mice. (A–C) The expression level of MDA and activities of SOD and GSH-Px were measured in mice hippocampus. (D–F) The expression level of MDA and activities of SOD and GSH-Px were measured in mice kidney. The data are expressed as mean ± SEM (n = 6–10). * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle group (Veh), one-way ANOVA post hoc Dunnett’s test.

Figure 6

Fucoidan regulated GSK3β-Nrf2-HO-1 signaling pathway in hippocampus and kidney of adenine-induced CKD mice (n = 8). (A–D) The mRNA expression of GSK3β, Nrf2, HO-1, and NQO-1 in the hippocampus. (E–H) The mRNA expression of GSK3β, Nrf2, HO-1, and NQO-1 in the kidney. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle group (Veh), one-way ANOVA post hoc Dunnett’s test.

Figure 7

Effects of fucoidan on inflammatory factors in hippocampus and kidney of adenine-induced CKD mice (n = 6–10). (A–C) TNFα, IL-1β, and IL-4 mRNA expression in the hippocampus; (D–F) TNFα, IL-1β, and IL-4 mRNA expression in the kidney. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle group (Veh), one-way ANOVA post hoc Dunnett’s test.

Figure 8

Effects of fucoidan on M1/M2 microglia or macrophage polarization in hippocampus and kidney of adenine-induced CKD mice (n = 6–10). (A–D) iNOS, TGFβ, Arg1, and CD206 mRNA expression in the hippocampus; (E–H) iNOS, TGFβ, Arg1, and CD206 mRNA expression in the kidney. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle group (Veh), one-way ANOVA post hoc Dunnett’s test.

Figure 9

Pearson correlation analysis between hippocampus gene expression and cognitive behavior. The mRNA qPCR analysis of Camk2n1 (A), SPP1 (B), Cd68 (C), GFAP (D), Apod (E), and Serpina3 (F) were performed.

Figure 10

Pearson correlation analysis between kidney gene expression and cognitive behavior. The mRNA qPCR analysis of Acy3 (A), Slc22a12 (B), Angptl7 (C), and Cxcl13 (D) were performed.