Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Abstract

Background: Alpha-klotho (α-KL) is not only related to the regulation of calcium-phosphorus metabolism, and fibrosis in chronic kidney disease (CKD), it is also involved in the regulation of many cognitive disorders.We conducted this study to investigate the effects of CKD on cognitive dysfunction and α-KL.Methods: Doxorubicin was used to induce a CKD model, which was validated by weight, 24-hour urine protein quantification, serum creatinine (Cr), blood urea nitrogen (BUN), and kidney hematoxylin-eosin (HE) staining. The Morris water maze (MWM) paradigm was used to assess the effects of CKD on cognitive behavior. The expression of α-KL in the hippocampus was detected using real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry (IHC).Results: (I) In the CKD group, the weight of the rats increased slowly (P<0.001), 24-hour urine protein increased (P<0.05), and Cr (P=0.026) and BUN levels (P=0.003) increased; (II) HE staining showed that in the CKD group there were changes in the structure, fibrosis, and inflammatory infiltration of the renal tissues, and changes in the structure, cell necrosis, and neuronal degeneration of the hippocampus; (III) in the MWM experiment, the escape latency of the CKD group was prolonged compared to that of the control group (P=0.043, 0.023), and the number of crossing the platform was reduced (P=0.003); (IV) in the CKD group, the expressions of α-KL messenger ribonucleic acid (P=0.0005) and α-KL protein (P=0.0005) in the hippocampus were downregulated. The IHC results showed that the expression of α-KL protein in the hippocampal region III cornus ammonis (CA3) of the CKD group region was also downregulated, and the α-KL-positive cells (P=0.019) and mean optical density (P=0.015) were decreased. Conclusions:The expression of α-KL appears to effect the cognitive function of CKD rats; thus, it may be a valuable target in the treatment of CKD with cognitive impairment.

Effects Of Quercetin and Vitamin D3 on Klotho Gene Expression in Relation to Neurological Functions in Chronic Kidney Disease Rat Model

“…All of these changes were improved in quercetin and/or vitamin D3 treated groups. In line with our result, Huang et al [26] noted in their study that the CKD group had hippocampus structural alterations, neuronal degeneration, and necrosis. Also, Ruiz et al [27] found that apoptosis of hippocampal neurons was observed in uremic animal models.…”

“…Correspondingly, other investigations have agreed with our findings showing that the pathogenesis and development of CKD are associated with Klotho downregulations in animal models [3,34]. In addition, Huang et al [26] reported that since α klotho expression appears to have an impact on the cognition of CKD rats, it could be a useful target for the prevention and therapy of impaired cognitive functions linked to CKD. Interestingly, Klotho expression level was significantly increased in the quercetin group in Bhatiya et al [35] study, which is in line with our finding.…”

Relationships between serum Klotho concentrations and cognitive performance among older chronic kidney disease patients with albuminuria in NHANES 2011-2014

“…The variation in Klotho gene is associated with bigger brain volume and better cognitive function in older adults ( 52 ). In CKD rats, the expression of α-Klotho significantly declined in the hippocampus, which might affect the cognitive function ( 53 ). Furthermore, elevating Klotho in mice enhanced synaptic plasticity, enriched synaptic receptor subunit for learning and memory, and intrinsic connectivity in fronto-parietal ( 20 , 54 ).…”