The Uremic Toxin Homocysteine Exacerbates the Brain Inflammation Induced by Renal Ischemia-Reperfusion in Mice

Abstract

Homocysteine (Hcy), a homologue of cysteine, is biosynthesized during methionine metabolism. Elevated plasma Hcy is associated with glomerular injury and considered as a risk factor for renal dysfunction, predicting incident chronic kidney disease. Hcy promotes oxidative stress, inflammation, and endothelial dysfunction. Acute kidney injury (AKI) is defined as a sudden decline in renal function and is important clinically due to the high mortality rate in AKI patients with multiple organs failure, including the brain. However, the cytotoxic role of Hcy on the brain following AKI is not directly shown. In this study, C57BL/6 mice were subjected to renal ischemia reperfusion (IR), one of the causes of AKI, and treated with vehicle or Hcy (0.2 mg/kg) to analyse the brain inflammation. IR mice showed a significant induction in plasma creatinine and Hcy levels, associated with tubular injury and neutrophil infiltration, and upregulation of pro-inflammatory cytokines and tubular apoptosis. Hcy treatment aggravated these renal damage and dysfunction by regulating cyclooxygenase-2 (COX-2), inhibitor of κB phosphorylation, and heme oxygenase-1. Consistently, Hcy treatment significantly increased expression of pro-inflammatory cytokines, glial fibrillary acidic protein, and COX-2 in the prefrontal cortex of IR mice. We conclude that Hcy treatment aggravated the renal dysfunction and enhanced IR-induced inflammatory cytokines and astrocyte activation in the brain. We propose that lowering plasma Hcy levels may attenuate neurological dysfunction found in patients with AKI.

Research on cognitive impairment and potential risk factors in peritoneal dialysis patients: An observational study

“…Residual renal function aids CAPD patients in maintaining stable volume status, reducing inflammatory responses, and clearing molecular substances, thus enhancing quality of life. Several studies [25][26][27] suggest that uremic toxin accumulation can trigger oxidative stress, chronic inflammation, and blood-brain barrier abnormalities, leading to cerebrovascular and neurological degeneration and cognitive decline. Residual renal function efficiently eliminates plasma macromolecular toxins, thereby delaying neuropathy.…”

“…Similarly, the education levels and blood uric acid levels in the observation group were significantly lower compared to the control group (P < .05) (Tables 1 and 2). Among the 268 CAPD patients evaluated, the prevalence of CI was 55.56%, with a median MoCA score of 25 (range: [22][23][24][25][26][27]. Across the spectrum of CI domains, delayed recall was diminished in all 156 cases (100%), linguistic capabilities were reduced in 94 www.md-journal.com cases (60.26%), and visual-spatial and executive functions significantly declined in 87 cases (55.06%), indicating multidimensional impairment.…”

Exploring the Link between Chronic Kidney Disease and Alzheimer’s Disease: A Longitudinal Follow-Up Study Using the Korean National Health Screening Cohort

“…Another potential mechanism linking CKD and AD involves the uremic toxin homocysteine [ 36 ]. Elevated plasma homocysteine levels are associated with both atrophic changes in the brain and glomerular injury [ 37 ]. This toxin may contribute to the pathogenesis of AD by activating N-methyl-D-aspartate receptors, leading to excessive calcium influx, increased oxidative stress, and inflammation within neurons, ultimately resulting in cell death [ 38 ].…”