Kynurenic acid, a key L-tryptophan-derived metabolite, protects the heart from an ischemic damage

Abstract

BackgroundRenal injury induces major changes in plasma and cardiac metabolites. We sought to identify a key metabolite that may affect cardiac mitochondria following an acute kidney injury (AKI) that may be harnessed to protect the heart following an acute ischemic event. Methods and ResultsMetabolomics profiling of cardiac lysates and plasma samples derived from rats that underwent AKI 1 or 7 days earlier by 5/6 nephrectomy versus sham-operated controls was performed. We detected only 26 differential metabolites in both heart and plasma samples at the two selected time points, relative to sham. Out of which, kynurenic acid (kynurenate, KYNA) seemed most relevant. Interestingly, KYNA given at 10 mM concentration significantly rescued the viability of H9C2 cardiac myoblast cells grown under anoxic conditions and largely improved their mitochondrial structure and function as determined by flow cytometry and cell staining with MitoTracker dyes. Moreover, KYNA diluted in the drinking water of animals induced with an acute myocardial infarction, highly enhanced their cardiac recovery according to echocardiography and histopathology. Conclusion and translational aspectKYNA may represent a key metabolite absorbed by the heart following AKI. This metabolite can enhance cardiac cell viability following an ischemic event in a mechanism that is mediated, at least in part, by the protection of the cardiac mitochondria. A short-term administration of KYNA may be highly beneficial in the treatment of the acute phase of kidney disease in order to attenuate progression to CRS and in ischemic cardiac conditions to reduce ischemic myocardial damage. HighlightsO_LIThe levels of the L-Tryptophan-derived metabolite, Kynurenic acid (KYNA), are significantly elevated in the heart and the plasma of animals induced with an acute kidney disease. C_LIO_LIKYNA rescues the viability of cardiac cells from an ischemic damage both in vitro and in vivo. C_LIO_LIKYNA can protect the structure & function of cardiac mitochondria in H9C2 cardiomyoblast cells upon exposure to anoxia. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=140 HEIGHT=200 SRC="FIGDIR/small/492275v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@f2a49aorg.highwire.dtl.DTLVardef@14a501org.highwire.dtl.DTLVardef@15d016aorg.highwire.dtl.DTLVardef@10800e7_HPS_FORMAT_FIGEXP M_FIG C_FIG