Abstract
Background and Aims
Chronic kidney disease (CKD) is getting prevalent and causes big burden to the health care systems worldwide. CKD-associated cognitive impairment (CI) not only influences the behave function, but also results in longer hospitalization and higher risk of mortality. Inflammation is an important pathogenesis of CKD and plays a crucial role in progression of CKD. In this study, we hypothesized that accumulated uremic toxins, especially indoxyl sulfate (IS) and P-cresyl sulfate (PCS) induce neuroinflammation via activation of NLRP3 inflammasome in the brain tissue of CKD animals. This study aims to delineate the crosstalk between uremic toxins and inflammation in CKD-induced CI.
Method
Eight-week-old male C57B6 wildtype and NLRP3 knockout mice received sham and 5/6 nephrectomy to mimic CKD status. AST-120 (Kremezin), a spherical carbon adsorbent, was given orally to mice to neutralize the accumulated uremic toxins. The Y-maze and Morris water maze (MWM) testes were applied to evaluate cognitive function, including the spatial, short-term and long-term memory in shame, CKD, and AST-120 treated CKD mice. HPLC was used to examine the concentration of IS and PCS in the serum and brain tissues. Western blot and immunohistochemistry stain were used to identify the protein expression of target molecules in the brain tissue.
Results
CKD mice showed impaired spatial, short-term and long-term memory; however, 10% AST-120 attenuated CKD-induced memory impairment (Figure 1). IS, but not PCS, elevated in the brain tissues, especially in the frontal cortex and hippocampus. AST-120 reduced CKD-induced IS elevation in the brain tissue, and also ameliorated NLRP3 inflammasome activation in the astrocytes in the frontal and hippocampus. Finally, NLRP3 deficiency reversed the CKD-induced memory impairment (Figure 2).
Conclusion
IS is the major uremic toxin that causes CI in CKD mice via activating NLRP3 inflammasome pathway in the brain tissue. However, AST-120 effectively ameliorates CKD-induced CI.
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