Altered Emotional Phenotypes in Chronic Kidney Disease Following 5/6 Nephrectomy

Abstract

Increased prevalence of chronic kidney disease (CKD) and neurological disorders including cerebrovascular disease, cognitive impairment, peripheral neuropathy, and dysfunction of central nervous system have been reported during the natural history of CKD. Psychological distress and depression are serious concerns in patients with CKD. However, the relevance of CKD due to decline in renal function and the pathophysiology of emotional deterioration is not clear. Male Sprague Dawley rats were divided into three groups: sham control, 5/6 nephrectomy at 4 weeks, and 5/6 nephrectomy at 10 weeks. Behavior tests, local field potentials, and histology and laboratory tests were conducted and investigated. We provided direct evidence showing that CKD rat models exhibited anxiogenic behaviors and depression-like phenotypes, along with altered hippocampal neural oscillations at 1-12 Hz. We generated CKD rat models by performing 5/6 nephrectomy, and identified higher level of serum creatinine and blood urea nitrogen (BUN) in CKD rats than in wild-type, depending on time. In addition, the level of α-smooth muscle actin (α-SMA) and collagen I for renal tissue was markedly elevated, with worsening fibrosis due to renal failures. The level of anxiety and depression-like behaviors increased in the 10-week CKD rat models compared with the 4-week rat models. In the recording of local field potentials, the power of delta (1-4 Hz), theta (4-7 Hz), and alpha rhythm (7-12 Hz) was significantly increased in the hippocampus of CKD rats compared with wild-type rats. Together, our findings indicated that anxiogenic behaviors and depression can be induced by CKD, and these abnormal symptoms can be worsened as the onset of CKD was prolonged. In conclusion, our results show that the hippocampus is vulnerable to uremia.

Keywords: astrogliosis; chronic kidney disease; emotional phenotypes; fibrosis; hippocampus; uremia.

Figure 1

Body weight and blood analysis of CKD and wild-type rat. The body weights of CKD rats were significantly reduced compared with the wild-type group (A). Serum creatinine and BUN levels were increased in CKD rat animal model more than in the wild-type (B,C). Data are presented as means ± standard errors of the mean. ** p < 0.01, *** p < 0.001, one-way analysis of variance.

Figure 2

Masson’s trichrome staining, and expression of α-SMA and collagen I in the kidneys of CKD and wild-type rats. Masson’s trichrome staining revealed progressive interstitial fibrosis at CKD 4 and 10 weeks more than in the wild-type (A,B). 10 weeks-recovered CKD rat models showed glomerulosclerosis collagen deposition in glomeruli (arrows) and injured tubules (*). Morphometric analysis for relative interstitial fibrosis: in CKD rats, increased α-SMA and collagen I immunoreactivities of the interstitium when compared with wild-type rats (A,C,D). In particular, densitometry of collagen I analysis were more enhanced at CKD 10 weeks rats than 4 weeks rats (D). Scale bar = 25 μm. Data are presented as means ± standard errors of the mean. * p < 0.05, ** p < 0.01, and *** p < 0.001, one-way analysis of variance.

Figure 3

Anxiety-related behaviors in CKD and wild-type rats. Representative diagram shows the overall experimental time schedules (A). Representative cumulative traces of navigation pathways of wild-type, CKD 4 week, and CKD 10 week rats during exploratory behavior in the open-field (B). Locomotor activity of CKD rat model was decreased as compared with wild-type littermates (C). Time spent in the central sector was increased in CKD models and number of defecation was reduced in the open field in CKD groups than wild-type group (D,E). Percentage of entries into the open arms and total number of entries in the elevated plus-maze were decreased in the CKD models compared with wild-type rats (F,G). In addition, light/dark transition number and total time in the light were lower in the CKD model than wild-type rats (H,I). Data are presented as means ± standard errors of the mean. * p < 0.05, ** p < 0.01, and *** p < 0.001, one-way analysis of variance.

Figure 4

Depression-like behaviors in CKD and wild-type rats. Increased percentages of immobility during forced swim test in CKD rats (A). Decreased latency to immobility of forced swim test in CKD rats (B). Data are presented as means ± standard errors of the mean. ** p < 0.01, *** p < 0.001, one-way analysis of variance.

Figure 5

Neural oscillations at 1–12 Hz in the CA1 region of hippocampus of CKD and wild-type rats. Representative LFP signals in the hippocampus of wild-type rats under urethane-induced anesthetic (A). The LFP profiles of each CKD rat showed epileptic discharges as large amplitude spikes of irregular sharp waves and multiple spikes (A). Power spectral analysis of the CKD rats revealed higher power at a lower frequency more than in the wild-type group (B). Hippocampal delta and theta oscillations were markedly elevated in the CKD 4 weeks and 10 weeks-recovered CKD rat model (C,D), hippocampal alpha rhythm was increased in the 10 week, but not the 4 weeks, recovered CKD rats (E). The average normalized power after CKD rats was stronger than in wild-type rats (F). Data are presented as means ± standard errors of the mean. * p < 0.05, ** p < 0.01, and *** p < 0.001, one-way analysis of variance (C–F).