Kynurenine Infusion Disrupts Normal Blood Pressure Circadian Rhythms

Kynurenine is the first stable product of tryptophan metabolism, and its level increases with age. Elevated kynurenine/tryptophan ratios have been implicated in many aging-related diseases including chronic kidney disease (CKD). We hypothesized that chronic infusion of kynurenine would induce alterations in renal-related parameters, such as blood pressure, sodium excretion and glomerular filtration rate (GFR), that could contribute to development of age-related CKD. In an IACUC-approved study, three-month-old male Sprague Dawley rats were instrumented with aortic and venous catheters, as well as telemeters for blood pressure monitoring, and then housed in metabolic cages for urine collection. Following a five-day control period, rats received continuous kynurenine infusion (5 mg/kg, 10 mg/kg, 50 mg/kg) or vehicle for 4 weeks. We found that GFR decreased after 2 weeks of KYN treatment [1.29 (n=5) vs. 1.51 (control, n=16) or 1.50 (vehicle, n=3) mL/min p=0.04]. The normal circadian rhythm for blood pressure was disrupted by all doses of kynurenine while heart rate maintained its normal diurnal pattern. Mean arterial pressure in kynurenine-treated rats tended to increase over time compared to vehicle-treated. Kynurenine infusion also induced increased water consumption. These data suggest that kynurenine treatment impacts renal function and may contribute to the development of CKD. Non-dipping blood pressure is a significant risk factor for cardiovascular disease, even in the context of normotension. Further studies will be needed to determine the mechanism of this effect.