Carnosinase-1 overexpression, but not aerobic exercise training, affects the development of diabetic nephropathy in BTBR ob/ob mice

Abstract

Manipulation of circulating histidine-containing dipeptides (HCD) has been shown to affect the development of diabetes and early-stage diabetic nephropathy (DN). The aim of the present study was to investigate whether such interventions, which potentially alter levels of circulating HCD, also affect the development of advanced-stage DN. Two interventions, aerobic exercise training and overexpression of the human carnosinase-1 (hCN1) enzyme, were tested. BTBR ob/ob mice were either subjected to aerobic exercise training (20 wk) or genetically manipulated to overexpress hCN1, and different diabetes- and DN-related markers were compared with control ob/ob and healthy (wild-type) mice. An acute exercise study was performed to elucidate the effect of obesity, acute running, and hCN1 overexpression on plasma HCD levels. Chronic aerobic exercise training did not affect the development of diabetes or DN, but hCN1 overexpression accelerated hyperlipidemia and aggravated the development of albuminuria, mesangial matrix expansion, and glomerular hypertrophy of ob/ob mice. In line, plasma, kidney, and muscle HCD were markedly lower in ob/ob versus wild-type mice, and plasma and kidney HCD in particular were lower in ob/ob hCN1 versus ob/ob mice but were unaffected by aerobic exercise. In conclusion, advanced glomerular damage is accelerated in mice overexpressing the hCN1 enzyme but not protected by chronic exercise training. Interestingly, we showed, for the first time, that the development of DN is closely linked to renal HCD availability. Further research will have to elucidate whether the stimulation of renal HCD levels can be a therapeutic strategy to reduce the risk for developing DN.

Unveiling the Hidden Therapeutic Potential of Carnosine, a Molecule with a Multimodal Mechanism of Action: A Position Paper

“…[ 109 , 118 ]. Furthermore, in the context of oral administration, at least five different units of measurement can be found within the research studies: mg or g/Kg [ 119 , 120 , 121 ], mg or g/L [ 98 , 115 , 116 ], mmol/L or Kg [ 99 , 122 , 123 , 124 ], mM [ 102 , 125 , 126 ], or % [ 127 , 128 , 129 ]. This, along with the wide range of treatment durations (from 1 [ 120 ] to 50 weeks [ 130 ]), reinforces the need for the alignment of future studies, which will likely lead to even more surprising results with regard to the therapeutic potential of carnosine.…”

Genotype Distribution of CNDP1 Polymorphisms in the Healthy Chinese Han Population: Association with HbA1c and Fasting Blood Glucose

“…Hence, carnosine can only transiently be detected in human serum, shortly after oral ingestion in individuals with low CN-1 activity [ 8 ]. Based on the foregoing, it was hypothesized that the CNDP1 (CTG) 5 homozygous genotype affords protection because it is associated with lower serum CN-1 activities which may facilitate higher tissue carnosine concentrations [ 8 , 9 ].…”

A Custom Target Next-Generation Sequencing 70-Gene Panel and Replication Study to Identify Genetic Markers of Diabetic Kidney Disease

“…CNDP1 encodes the enzyme responsible for the degradation of carnosine, a peptide with renoprotective properties. This gene has been pointed out as an important locus for DKD [ 27 ], as its overexpression, enhancing carnosine metabolism, may favor the development of this complication [ 28 ]. The identified rs4891564 SNP is located in the regulatory region of the gene and hence it holds the potential to affect its expression.…”