Altered KLOTHO and NF-κB-TNF-α Signaling Are Correlated with Nephrectomy-Induced Cognitive Impairment in Rats.

Sabrina Degaspari,Ana Elisa Böhmer,Diana Zukas Andreotti,Carmen Branco Tzanno-Martins,Hudson De Souza Buck,Clarice Kazue Fujihara,Ana Maria Marques Orellana,Roberto Zatz,Carolina Demarchi Munhoz,Cristoforo Scavone,João Paulo Branco-Martins,Larissa De Sá Lima,Tania Araujo Viel,Elisa Mitiko Kawamoto

doi:10.1371/journal.pone.0125271

Abstract

Renal insufficiency can have a negative impact on cognitive function. Neuroinflammation and changes in klotho levels associate with chronic kidney disease (CKD) and may play a role in the development of cognitive impairment (CI). The present study evaluates the correlation of cognitive deficits with neuroinflammation and soluble KLOTHO in the cerebral spinal fluid (CSF) and brain tissue of nephrectomized rats (Nx), with 5/6 renal mass ablation. Nx and sham Munich Wistar rats were tested over 4 months for locomotor activity, as well as inhibitory avoidance or novel object recognition, which started 30 days after the surgery. EMSA for Nuclear factor-κB and MILLIPLEXMAP or ELISA kit were used to evaluate cytokines, glucocorticoid and KLOTHO levels. Nx animals that showed a loss in aversive-related memory and attention were included in the CI group (Nx-CI) (n=14) and compared to animals with intact learning (Nx-M n=12 and Sham n=20 groups). CSF and tissue samples were collected 24 hours after the last behavioral test. The results show that the Nx-groups have increased NF-κB binding activity and tumor necrosis factor-alpha (TNF-α) levels in the hippocampus and frontal cortex, with these changes more pronounced in the Nx-CI group frontal cortex. In addition, the Nx-CI group showed significantly increased CSF glucocorticoid levels and TNF-α /IL-10 ratio compared to the Sham group. Klotho levels were decreased in Nx-CI frontal cortex but not in hippocampus, when compared to Nx-M and Sham groups. Overall, these results suggest that neuroinflammation mediated by frontal cortex NF-κB, TNF-α and KLOTHO signaling may contribute to Nx-induced CI in rats.

Highlights

Chronic kidney disease (CKD) is a public health problem that has been related to cognitive decline in recent years [1, 2]
As this data indicate a possibility of inflammatory pattern linked to TNFα in the cerebral spinal fluid (CSF) of Nx-Cognitive impairment (CI) rats, we evaluated changes induced by Nx on hippocampus and frontal cortex TNFα levels
It is believed that these cognitive changes are related to vascular changes in the CNS due to CKD, as well as to changes triggered by hemodialysis procedures [30, 31]

Summary

Introduction

Chronic kidney disease (CKD) is a public health problem that has been related to cognitive decline in recent years [1, 2]. Increased systemic inflammation, including increased plasma proinflammatory cytokines and reactive oxygen species (ROS), are found in CKD patients [6]. It is known that cytokines play an important role in the molecular mechanisms underlying memory and cognitive processes [8, 9]. Systemic administration of the pro-inflammatory cytokine tumor necrosis factor (TNF-α) reduces cell proliferation in the hippocampus [12]. Secreted Klotho functions as a humoral factor that regulates activity of multiple glycoproteins on the cell surface, including ion channels and growth factor receptors such as insulin/insulin-like growth factor-1 receptors (IGF1) [22, 23]. We provide the first evidence showing that changes in NF-KB activity and TNF-α-KLOTHO signaling play an important role in nephrectomized (Nx) induced CI in a rodent CKD model

Material and Methods

Results

Discussion