title: 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.
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Degaspari
authors.affiliation: Centro Integrado de Nefrologia, São Paulo, Brazil.
authors.forename: Carmen Branco
authors.initials: CB
authors.lastname: Tzanno-Martins
authors.affiliation: Renal Division, Department of Clinical Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Clarice Kazue
authors.initials: CK
authors.lastname: Fujihara
authors.affiliation: Renal Division, Department of Clinical Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Zatz
authors.affiliation: Centro Integrado de Nefrologia, São Paulo, Brazil.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Branco-Martins
authors.affiliation: School of Arts, Sciences and Humanities, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Tania Araujo
authors.initials: TA
authors.lastname: Viel
authors.affiliation: Department of Physiological Sciences, Santa Casa de São Paulo Medical School, São Paulo 01221-020, Brazil.
authors.forename: Hudson de Souza
authors.initials: Hde S
authors.lastname: Buck
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Ana Maria Marques
authors.initials: AM
authors.lastname: Orellana
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Ana Elisa
authors.initials: AE
authors.lastname: Böhmer
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Larissa de Sá
authors.initials: Lde S
authors.lastname: Lima
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Diana Zukas
authors.initials: DZ
authors.lastname: Andreotti
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Carolina Demarchi
authors.initials: CD
authors.lastname: Munhoz
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Scavone
authors.affiliation: Molecular Neuropharmacology Laboratory, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.
authors.forename: Elisa Mitiko
authors.initials: EM
authors.lastname: Kawamoto
mesh_terms: D000818:Animals; D001288:Attention; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism*; D005966:Glucuronidase / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D008568:Memory; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009392:Nephrectomy / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005966:Glucuronidase; D000090265:Klotho Proteins