Brain-kidney crosstalk

Brain-kidney crosstalk

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

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.

In our clinical study we found a decrease in the protein levels in the frontal cortex of Nx-CI animals compared with Nx-M and Sham. Relevant to this observation is the significantly increased TNF-α levels and NF-kB activation in the same brain area, when compared to Nx-M and sham groups. Studies from our laboratory showed that Hemodialysis (HD) patients without cognitive deficit show an increase in TNF-α serum levels. In addition, there is a correlation of high TNF-α with a presence of low serum Klotho levels in HD patients with cognitive deficit as evaluated by Modified Mini Exam of Mental State (3MS) and Kidney Disease Quality of Life (KDQOL-sf) (unpublished data). This suggests an interaction between KLOTHO and inflammatory signaling over the course of CI, which is supported by the Pearson’s correlation showing a significant negative association of TNFα and KLOTHO levels in frontal cortex of Nx groups.