Key result
TLR4/NF-κB inhibition ameliorates cardiorenal dysfunction and suppresses adverse myocardial remodeling in uremic cardiomyopathy.
Why the study?
The internal interactive regulatory network between TLR4/NF-κB inflammatory signaling and autophagy dysregulation in the pathogenesis of uremic cardiomyopathy had not been fully clarified.
Does inhibition of TLR4 or NF-κB improve cardiac and renal function and reduce myocardial injury in a rat model of uremic cardiomyopathy?
Does inhibition of TLR4 or NF-κB improve cardiac and renal function and reduce myocardial injury in a rat model of uremic cardiomyopathy?
Inhibition of the TLR4/NF-κB signaling axis alleviates renal injury, inflammation, and myocardial damage in a rat model of uremic cardiomyopathy by modulating autophagy.
TLR4/NF-κB inhibition improves rat uremic cardiomyopathy; hypothesis-generating, leaves open clinical translation.
Background: Uremic cardiomyopathy (UCM) is a severe and irreversible cardiovascular complication that commonly occurs in patients with end-stage renal disease and is associated with poor prognosis. Both toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) inflammatory signaling and autophagy dysregulation are critically implicated in the pathogenesis of UCM; however, their internal interactive regulatory network has not been fully clarified. This study was designed to explore the role of TLR4/NF-κB axis in regulating myocardial autophagy and pathological injury in UCM.Methods: Based on 24 Sprague-Dawley rats, control (sham operation), UCM (5/6 nephrectomy), UCM+Resatorvid (TAK-242, TLR4 inhibitor, 2 mg/kg/day s.c.), and UCM+JSH23 (NF-κB inhibitor, 3 mg/kg/day s.c.) groups were constructed (n = 6/group). Following 10 weeks of observation, renal function, systemic inflammation, cardiac performance, myocardial histopathology, TLR4/myeloid differentiation factor 88 (MyD88) pathway and autophagy-related protein expression were systematically evaluated.Results: UCM model rats exhibited significant renal function impairment, elevated systemic inflammation, deteriorated cardiac function, as well as severe myocardial hypertrophy, interstitial fibrosis, and increased cardiomyocyte apoptosis (p < 0.05). These pathological changes were accompanied by excessive activation of the TLR4/MyD88/p-P65 signaling cascade and obvious changes in autophagy-related molecular expression, as evidenced by an elevated Microtubule-associated protein light chain 3 II (LC3II)/LC3I ratio and higher Beclin 1 levels (p < 0.001). Both TAK-242 and JSH23 treatment effectively ameliorated renal and cardiac dysfunction, suppressed adverse myocardial pathological remodeling, and reversed autophagy-related protein expression in UCM rats (p < 0.05).Conclusions: The TLR4/NF-κB signaling axis may contribute to UCM progression via modulating the expression of autophagy-associated proteins. Concurrent inhibition of this axis was correlated with alleviation of renal injury, inflammation and myocardial damage, indicating a potential therapeutic strategy for UCM.
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Zhu et al. (2026) studied Uremic cardiomyopathy (n=24). TAK-242 and JSH23 vs. UCM model (5/6 nephrectomy) and sham control was evaluated on Renal and cardiac dysfunction, myocardial pathological remodeling, and autophagy-related protein expression (p=<0.05). Inhibition of TLR4/NF-κB signaling with TAK-242 or JSH23 ameliorated renal and cardiac dysfunction and suppressed adverse myocardial remodeling in uremic cardiomyopathy rats.
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