Energy metabolism, proteotoxic stress and age-related dysfunction – Protection by carnosine

Hipkiss, Alan R.

doi:10.1016/j.mam.2011.10.004

Cited by 46 publications

(40 citation statements)

References 178 publications

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“…Carnosine scavenges carbonyls (Barski et al 2013;Negre-Salvayre et al 2008;Vistoli et al 2009), inhibits glycation (Alhamdani et al 2007) and acts as ACE inhibitor (Hou et al 2003;Nakagawa et al 2006). Its function as antioxidant is debated (Babizhayev et al 2013;Decker et al 2000;Hipkiss 2011;Mozdan et al 2005;Velez et al 2008). Anserine has been shown to scavenge carbonyls (Aldini et al 2005), to act as antioxidant (Kohen et al 1988), and to reduce renal sympathetic nerve activity and blood pressure (Tanida et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Carnosine metabolism in diabetes is altered by reactive metabolites

et al. 2015

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Carnosinase 1 (CN1) contributes to diabetic nephropathy by cleaving histidine-dipeptides which scavenge reactive oxygen and carbonyl species and increase nitric oxide (NO) production. In diabetic mice renal CN1 activity is increased, the regulatory mechanisms are unknown. We therefore analysed the in vitro and in vivo regulation of CN1 activity using recombinant and human CN1, and the db/db mouse model of diabetes. Glucose, leptin and insulin did not modify recombinant and human CN1 activity in vitro, glucose did not alter renal CN1 activity of WT or db/db mice ex vivo. Reactive metabolite methylglyoxal and Fenton reagent carbonylated recombinant CN1 and doubled CN1 efficiency. NO S-nitrosylated CN1 and decreased CN1 efficiency for carnosine by 70 % (p < 0.01), but not for anserine. Both CN1 cysteine residues were nitrosylated, the cysteine at position 102 but not at position 229 regulated CN1 activities. In db/db mice, renal CN1 mRNA and protein levels were similar as in non-diabetic controls, CN1 efficiency 1.9 and 1.6 fold higher for carnosine and anserine. Renal carbonyl stress was strongly increased and NO production halved, CN1 highly carbonylated and less S-nitrosylated compared to WT mice. GSH and NO2/3 concentrations were reduced and inversely related with carnosine degradation rate (r = -0.82/-0.85). Thus, reactive metabolites of diabetes upregulate CN1 activity by post-translational modifications, and thus decrease the availability of reactive metabolite-scavenging histidine dipeptides in the kidney in a positive feedback loop. Interference with this vicious circle may represent a new therapeutic target for mitigation of DN.

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Section: Introductionmentioning

confidence: 99%

Carnosine metabolism in diabetes is altered by reactive metabolites

et al. 2015

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“…Other mechanisms must be active to explain the repeatedly observed nephroprotective action of carnosine supplementation in diabetic rodents and the observed association of CN1 activity defining CNDP1 genotypes and the risk of nephropathy in diabetic humans. The function of carnosine as an antioxidant, as discussed in the literature [48-52], is controversial and its role in diabetes requires further investigation.…”

Section: Resultsmentioning

confidence: 99%

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Weigand

Singler

Fleming

et al. 2018

Cell Physiol Biochem

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Background/Aims: Reactive dicarbonyl compounds, such as methylglyoxal (MG), contribute to diabetic complications. MG-scavenging capacities of carnosine and anserine, which have been shown to mitigate diabetic nephropathy, were evaluated in vitro and in vivo. Methods: MG-induced cell toxicity was characterized by MTT and MG-H1-formation, scavenging abilities by Western Blot and NMR spectroscopies, cellular carnosine transport by qPCR and microplate luminescence and carnosine concentration by HPLC. Results: In vitro, carnosine and anserine dose-dependently reduced N-carboxyethyl lysine (CEL) and advanced glycation end products (AGEs) formation. NMR studies revealed the formation of oligo/polymeric products of MG catalyzed by carnosine or anserine. MG toxicity (0.3-1 mM) was dose-dependent for podocytes, tubular and mesangial cells whereas low MG levels (0.2 mM) resulted in increased cell viability in podocytes (143±13%, p<0.001) and tubular cells (129±3%, p<0.001). Incubation with carnosine/anserine did not reduce MG-induced toxicity, independent of incubation times and across large ranges of MG to carnosine/anserine ratios. Cellular carnosine uptake was low (<0.1% in 20 hours) and cellular carnosine concentrations remained unaffected. The putative carnosine transporter PHT1 along with the taurine transporter (TauT) was expressed in all cell types while PEPT1, PEPT2 and PHT2, also belonging to the proton-coupled oligopeptide transporter (POT) family, were only expressed in tubular cells. Conclusion: While carnosine and anserine catalyze the formation of MG oligo/polymers, the molar ratios required for protection from MG-induced cellular toxicity are not achievable in renal cells. The effect of carnosine in vivo, to mitigate diabetic nephropathy may therefore be independent upon its ability to scavenge MG and/or carnosine is mainly acting extracellularly.

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“…Rapamycin, an immune-suppressor, has been shown to exert substantial anti-ageing effects in a number of organisms, from yeast to rodents. It has previously been suggested [54] that carnosine could be a rapamycin mimetic (rapalogue) and there is some recent evidence which supports this speculation [55].…”

Section: Mtor Inhibitionmentioning

confidence: 90%