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

doi:10.1152/ajprenal.00329.2019. 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. 'Iwo interventions, aerobic exercise training and overexpression of the human carnosinase-1 (hCNI) enzyme, were tested. BTBR ob/ob mice were either subjected to aerobic exercise training (20 wk) or genetically manipulated to overexpress hCNi, and different diabetes- and DNrelated 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 hCNI overexpression on plasma HCD levels. Chronic aerobic exercise training did not affect the development of diabetes or DN, but hCNI overexpression accelerated hyperlipidemia and aggravated the development of alburninuria, mesangial matrix expansion, and glomerular hypertrophy- of ob/ob mice. In line, plasma, kidney, and muscle 11CD were markedly lower in oh/oh versus wild -type mice, and plasma and kidney HCD in particular were lower in ob/ob hCNI versus ob/ob mice but were unaffected by aerobic exercise. In conclusion, advanced glomerular damage is accelerated in mice overexpressing the hCNI 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 he a therapeutic strategy to reduce the risk for developing DN.