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Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat.

ABSTRACT: Kir5.1 is an inwardly rectifying potassium (Kir) channel subunit abundantly expressed in the kidney and brain. We previously established the physiologic consequences of a Kcnj16 (gene encoding Kir5.1) knockout in the Dahl salt-sensitive rat (SSKcnj16-/-), which caused electrolyte/pH dysregulation and high-salt diet-induced mortality. Since Kir channel gene mutations may alter neuronal excitability and are linked to human seizure disorders, we hypothesized that SSKcnj16-/- rats would exhibit neurological phenotypes, including increased susceptibility to seizures. SSKcnj16-/- rats exhibited increased light sensitivity (fMRI) and reproducible sound-induced tonic-clonic audiogenic seizures confirmed by electroencephalography. Repeated seizure induction altered behavior, exacerbated hypokalemia, and led to approximately 38% mortality in male SSKcnj16-/- rats. Dietary potassium supplementation did not prevent audiogenic seizures but mitigated hypokalemia and prevented mortality induced by repeated seizures. These results reveal a distinct, nonredundant role for Kir5.1 channels in the brain, introduce a rat model of audiogenic seizures, and suggest that yet-to-be identified mutations in Kcnj16 may cause or contribute to seizure disorders.

SUBMITTER: Manis AD

PROVIDER: S-EPMC7821607 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat.

Manis Anna D AD Palygin Oleg O Isaeva Elena E Levchenko Vladislav V LaViolette Peter S PS Pavlov Tengis S TS Hodges Matthew R MR Staruschenko Alexander A

JCI insight 20210111 1

Kir5.1 is an inwardly rectifying potassium (Kir) channel subunit abundantly expressed in the kidney and brain. We previously established the physiologic consequences of a Kcnj16 (gene encoding Kir5.1) knockout in the Dahl salt-sensitive rat (SSKcnj16-/-), which caused electrolyte/pH dysregulation and high-salt diet-induced mortality. Since Kir channel gene mutations may alter neuronal excitability and are linked to human seizure disorders, we hypothesized that SSKcnj16-/- rats would exhibit neur ...[more]

PMID: 33232300

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Project description:The SS-16(BN)/Mcwi consomic rat was produced by the introgression of chromosome 16 from the Brown Norway (BN/NHsdMcwi) rat onto the genetic background of the Dahl salt-sensitive (SS/Mcwi) rat by marker-assisted breeding. We have previously shown that the normotensive SS-16(BN)/Mcwi consomic strain is better protected from developing left ventricular dysfunction and fibrosis with aging than the hypertensive SS/Mcwi parental strain; however, the mechanism of this protection was not clear since the SS-16(BN)/Mcwi had both lowered blood pressure and an altered genetic background compared with SS/Mcwi. Microarray analysis of SS-16(BN)/Mcwi and SS/Mcwi left ventricle tissue and subsequent protein pathway analysis were used to identify alterations in gene expression in signaling pathways involved with the observed cardioprotection on the SS background. The SS-16(BN)/Mcwi rats exhibited much higher mRNA levels of expression of transcription factor JunD, a gene found on chromosome 16. Additionally, high levels of differential gene expression were found in pathways involved with angiogenesis, oxidative stress, and growth factor signaling. We tested the physiological relevance of these pathways by experimentally determining the responsiveness of neonatal cardiomyocytes to factors from identified pathways and found that cells isolated from SS-16(BN)/Mcwi rats had a greater growth response to epidermal growth factor and endothelin-1 than those from parental SS/Mcwi. We also demonstrate that the SS-16(BN)/Mcwi is better protected from developing fibrosis with surgically elevated afterload than other normotensive strains, indicating that gene-gene interactions resulting from BN chromosomal substitution confer specific cardioprotection. When combined with our previous findings, these data suggest that that SS-16(BN)/Mcwi may have an increased angiogenic potential and better protection from oxidative stress than the parental SS/Mcwi strain. Additionally, the early transient idiopathic left ventricular hypertrophy in the SS-16(BN)/Mcwi may be related to altered myocyte sensitivity to growth factors.

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Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat.

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Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat.

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