High Serum Phosphate Promotes Cognitive Impairment in Uremic Rats via Mediating Vascular Calcification

Cognitive impairment (CI) is common in patients with end-stage renal disease, but the mechanism of uremia-associated CI is poorly recognized.

In this study, we constructed uremic rat models, treated with high-level phosphate (Pi) and the vascular calcification (VC) inhibitor, sodium thiosulphate (STP). We assessed the spatial learning and memory by the Morris Water Maze test, detected the VC by histological staining, and monitored the osteogenic factors alkaline phosphatase (ALP) and Runx2 expressions in Uremia + Pi and Uremia + Pi + STP rats through qPCR, Western blotting analysis, and immunohistochemistry analysis. Moreover, we examined the calcium content and the ALP and Runx2 expressions in vascular smooth muscle cells (VSMCs) treated with Pi and STP.

The results showed that both the learning and memory abilities and the spatial exploration ability of the rats in the Uremia + Pi group were significantly decreased with enhanced expressions of ALP and Runx2, calcium content, and ALP activity; however, STP supplementation significantly alleviated the spatial learning and memory damage, reduced the ALP and Runx2 expressions, calcium content, and ALP activity. Moreover, Pi treatment significantly increased the calcium and malondialdehyde content in VSMCs, as well as ALP and Runx2 expressions. STP addition reversed these changes, indicating that a high phosphate level induced VC development.

Taken together, these results indicated that elevated serum phosphate might promote VC in uremic rats by activating the expressions of ALP and Runx2, thereby causing damage to the kidneys and uremia-associated complications such as CI. Therefore, this study improved the understanding to possible pathogenic mechanisms of uremia-induced CI, and will be beneficial to optimize the prevention and treatment strategy for CI in uremic patients.