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

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.

The relevance of α-KLOTHO to the central nervous system: Some key questions

“…Our observation of decreased α-Klotho protein in the pre-frontal cortex of nephrectomized mice (Degaspari et al, 2015) indicates that kidney damage can affect α-Klotho expression in other organs, and adds to the mounting evidence that renal impairment impacts on cognition. However, our work also raises the questions of how kidney damage is able to elicit decreased brain α-Klotho, and whether this is dependent upon loss of serum α-Klotho.…”

“…α-Klotho mRNA is also detectible, albeit at lower levels, in several other brain regions, including cortex, hippocampus, cerebellum, striatum, substantia nigra, olfactory bulb and medulla (Brobey et al, 2015;Clinton et al, 2013;German et al, 6 2012; Li et al, 2004). Lack of suitable antibodies have hampered studies of α-Klotho expression at the protein level, but are nonetheless consistent with expression in multiple brain regions, and in both neurons and oligodendrocytes (Brobey et al, 2015;Clinton et al, 2013;Degaspari et al, 2015;German et al, 2012;Li et al, 2004). Since there is no evidence α-Klotho can cross the blood-brain barrier and there is very little fluid exchange between the CSF and the interstitial fluid of the brain parenchyma, we can be reasonably confident that α-Klotho protein detectable in the brain ('brain α-Klotho') has been expressed locally.…”

“…Intriguingly, in comparison to both sham surgery controls and nephrectomized animals that did not develop memory impairment, these animals displayed a marked decrease in levels of α-Klotho in the pre-frontal cortex. Thus, in addition to causing cognitive impairment and decreasing serum α-Klotho, kidney damage also reduces α-Klotho in the brains of animals, a decrease that is associated with cognitive impairment (Degaspari et al, 2015).…”

The systemic nature of CKD

“…Conventional risk factors for cardiovascular disease (such as old age, hypertension, diabetes, dyslipidaemia and atrial fibrillation) might induce neurological disorders in CKD, mainly through microvascular disease. Risk factors associated with low eGFR, including albuminuria 235 , altered NF-κB-TNF and Klotho signalling 236 and increased levels of β2-microglobulin 237 , are independently associated with structural and functional cerebral changes. In the systemic scenario of CKD, which is characterized by renal and cerebrovascular inflammation, endothelial dysfunction, excess RAS activation and oxidative stress 234 , the levels of a substantial number of neuromediators and endocrine factors (such as β-endorphin, methionine-enkephalin, adrenomedullin and neuropeptide Y) are temporally (circadian rhythms) and quantitatively altered 229,238 .…”

αKlotho and Chronic Kidney Disease

“…It is a main functional form in the circulation (Hu, Shi, Zhang, et al, 2015; Hu, Shi, Zhang, Pastor, et al, 2010; Hu, Shi, Zhang, Quinones, et al, 2010; Imura et al, 2004; Kurosu et al, 2005). Soluble αKlotho protein is also present in cerebrospinal fluid (Chen et al, 2015; Degaspari et al, 2015; Emami Aleagha et al, 2015; Imura et al, 2004; Semba et al, 2014) and urine of mammals (Akimoto et al, 2012; Hu, Shi, Zhang, Pastor, et al, 2010; Hu et al, 2011; Lau et al, 2012). Soluble αKlotho functions as a circulating substance exerting multiple systemic biological actions on distant organs and directly protects cells against a variety of insults including hypoxia, hyperoxia, oxidative stress, and cytotoxic medication and suppresses apoptosis (Cheng et al, 2015; Hu, Shi, Cho, et al, 2013; Panesso et al, 2014; Ravikumar et al, 2014; Sun et al, 2015; Wang et al, 2013).…”