Chronic renal function impairment induced cognitive changes and related pathology in muce after unilateral obstruction (UUO) surgery

Abstract

Background: Chronic kidney disease is associated with cognitive impairment. While the pathophysiology remains unclear, it has been suggested that it shares some similarity to those in Alzheimer’s disease. Currently, most studies in this area used the 5/6 nephrectomy and high adenine diet to induce renal impairment in rat or mice. Our group had successfully used the unilateral ureteral obstruction (UUO) mice as an animal model to study the cognitive changes and related pathology. Method: Eight-week-old male C57BL/6N mice received the UUO operation with double ligation of their left ureter under general anesthesia. Sham operated mice received the same experimental procedure without ureteral obstruction. Cognitive and behavioral tests were performed to examine potential changes in cognition and other behavior 2, 4 or 12 weeks after the surgery. The serum, kidneys and brains were harvested for the detection of systematic inflammation markers and neurodegenerative changes. Result: Progressive renal impairment were observed after the UUO surgery. Systematic inflammation was evident by detecting an increase in C-reactive protein and TNF-a levels in the UUO mice. These mice also showed a significantly worse performance in the novel object recognition test, Y-maze test, and puzzle box test when compared to the sham control, indicated cognitive impairment. Reduction in synaptic proteins such as synapsin-1, synaptophysin, synaptotagmin, PSD95, NMDAR2B and AMPAR, elevation of Nrf2 and 8-Hydroxyguanosine and hyperphosphorylation of tau were found in their hippocampus. Conclusion: We have characterized the cognitive and neuropathological changes in the UUO mice. This mouse model can be used for studying chronic kidney disease-induced cognitive impairment and may have an implication for understanding the pathogenesis of Alzheimer’s disease.