Key result
1-Methylhistidine reduces myocardial TUNEL positivity by an absolute ~7% in type 3 cardiorenal syndrome.
Why the study?
The contribution of acute kidney injury-associated metabolic remodeling to early myocardial inflammation in type 3 cardiorenal syndrome was poorly understood.
Does 1-Methylhistidine attenuate early myocardial inflammation and improve cardiac function in a rat model of type 3 cardiorenal syndrome?
Does 1-Methylhistidine attenuate early myocardial inflammation and improve cardiac function in a rat model of type 3 cardiorenal syndrome?
Absolute Event Rate: 9.68% vs 16.61%
p-value: p=<0.05
1-Methylhistidine acts as a protective metabolite that mitigates early myocardial inflammation and oxidative stress in type 3 cardiorenal syndrome by stabilizing p105 and dampening NF-κB signaling.
Hypothesis-generating for 1-methylhistidine in experimental type 3 cardiorenal syndrome; leaves open clinical translation pending human studies.
Type 3 cardiorenal syndrome (CRS3) is characterized by cardiac injury or dysfunction secondary to acute kidney injury (AKI), yet the contribution of AKI-associated metabolic remodeling to early myocardial inflammation remains poorly understood. Here, paired serum and myocardial untargeted metabolomics identified 1-methylhistidine (1-MH) as a metabolite elevated in both compartments, with the highest variable importance in projection score in serum. Exogenous 1-MH improved the E/A ratio and attenuated myocardial inflammation and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positivity in rats with CRS3. Similar protective effects were observed in a separate post-ischemic cohort in which 1-MH was administered immediately after renal reperfusion. In CRS serum-exposed H9c2 cells, 1-MH reduced reactive oxygen species-associated fluorescence, malondialdehyde content, and intracellular Fe 2+ levels. Transcriptomic profiling showed that 1-MH suppressed inflammatory signaling, accompanied by changes in oxidative metabolism. Integration of these transcriptomic signatures with target prediction prioritized NFKB1/p105, while ensemble docking identified recurrent candidate interaction regions within p105. Cellular thermal shift assays showed a concentration-related increase in p105 thermal stability following 1-MH treatment. 1-MH increased p105 abundance while reducing total p50 abundance and nuclear p50 accumulation. p105 overexpression increased p50 abundance and the expression of inflammatory transcripts and proteins suppressed by 1-MH. These findings demonstrate that 1-MH attenuates early myocardial inflammation in CRS3 and reduces oxidative stress-related changes in CRS serum-exposed H9c2 cells. These functional results support modulation of the p105/p50 NF-κB axis and identify p105 as a molecular link between AKI-associated metabolic remodeling and myocardial inflammatory signaling.
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Zhang et al. (2026) studied Type 3 Cardiorenal Syndrome (CRS3). 1-Methylhistidine (1-MH) vs. Saline or Vehicle was evaluated on Myocardial TUNEL positivity (p=<0.05). 1-Methylhistidine significantly reduced myocardial TUNEL positivity from 16.61% to 9.68% and attenuated early myocardial inflammation in rats with type 3 cardiorenal syndrome.
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