INTRODUCING CYP2C19 TRANSGENIC KNOCK-IN MICE AS A MODEL TO STUDYING COGNITIVE IMPAIRMENT IN CHRONIC KIDNEY DISEASE

Chronic kidney disease (CKD), a condition characterized by the gradual loss of kidney function over time, affects more than 10% of the general population worldwide amounting to about 800 million individuals. Neurocognitive disorders such as cognitive impairment (CI) and mood disorders such as depression and anxiety are an emerging and significant problem in CKD, affecting many patients, and are exacerbated by worsening kidney function independent of other confounding factors. In the absence of a deeper mechanistic understanding of the specific causes and mechanisms underlying cognitive decline in patients with CKD, it is of overall importance to introduce suitable animal models to effectively study cognitive impairment in CKD. The method used to induce CKD should not significantly and primarily affect non-kidney organs, especially the central nervous system. Transgenic knock-in CYP2C19 mice were demonstrated to display motor and mood disorder; however, their cognitive abilities were not well tested. Having that in mind we aimed to explore cognitive characteristics and kidney function of this knock-in mouse strain. In order to introduce it as a CKD model, we compared it to classical subtotal nephrectomy (5/6Nx) surgical model for CKD.

Transgenic knock-in (TG) CYP2C19 mice (N=17) were used for testing cognitive behaviour and kidney function (plasma and 24h urine levels of urea, creatinine, albumin and proteins). Wild type (WT) mice (N=25) 8-weeks-old were used for surgical subtotal nephrectomy (N= 13) or sham operation (N=12), and wild type non-operated mice were used as controls (N=25). Six weeks were allowed for development CKD in 5/6Nx mice and behavioural testing for learning and memory were performed, while blood, 24h urine and kidney tissue were collected afterwards. Histological analysis of kidney tissue was performed in all groups.

Behaviorl analysis: Novel object recognition test (NORT) showed that TG mice did not discriminate familiar and novel object unlikely WT male (p˂0.05) and female WT mice (p˂0.1).    Social recognition test (SRT) showed impaired social memory for TG mice and preserved in both male WT (p˂0.001) and female mice (p˂0.05). Nephrectomy model also demonstrated impaired spatial and social memory compared to control mice that showed increased time spent with novel object (p˂0.05), and novel mice (p˂0.001). Biochemical analysis: TG mice plasma and urine did not show difference in urea, creatinine, proteins and albumin levels. As expected, 5/&Nx mice had all the biochemical features of CKD – albuminuria, increased plasma urea and creatinine and reduced albumin compared to controls. Lastly, kidney histological analysis demonstrated interstitial fibrosis, tubular atrophy and chronic glomerular lesions in nephrectomy model, while TG mice had no evident histological changes in kidney tissue.

TG CYP2C19 mouse model can be used to study cognitive impairment in CKD in parallel with classical 5/6Nx model to discriminate factors affecting cognition independently of CKD stage and development. It can also be used as control group that has preserved kidney function but has spatial and social memory impairment. Our study suggests using both models for exploring novel therapies for CKD that would preserve/improve cognition in these patients.