Kidney Mass Reduction Leads to l ‐Arginine Metabolism‐Dependent Blood Pressure Increase in Mice

Abstract

Background Uninephrectomy (UNX) is performed for various reasons, including kidney cancer or donation. Kidneys being the main site of l ‐arginine production in the body, we tested whether UNX mediated kidney mass reduction impacts l ‐arginine metabolism and thereby nitric oxide production and blood pressure regulation in mice. Methods and Results In a first series of experiments, we observed a significant increase in arterial blood pressure 8 days post‐UNX in female and not in male mice. Further experimental series were performed in female mice, and the blood pressure increase was confirmed by telemetry. l ‐citrulline, that is used in the kidney to produce l ‐arginine, was elevated post‐UNX as was also asymmetric dimethylarginine, an inhibitor of nitric oxide synthase that competes with l ‐arginine and is a marker for renal failure. Interestingly, the UNX‐induced blood pressure increase was prevented by supplementation of the diet with 5% of the l ‐arginine precursor, l ‐citrulline. Because l ‐arginine is metabolized in the kidney and other peripheral tissues by arginase‐2, we tested whether the lack of this metabolic pathway also compensates for decreased l ‐arginine production in the kidney and/or for local nitric oxide synthase inhibition and consecutive blood pressure increase. Indeed, upon uninephrectomy, arginase‐2 knockout mice (Arg‐2 −/− ) neither displayed an increase in asymmetric dimethylarginine and l ‐citrulline plasma levels nor a significant increase in blood pressure. Conclusions UNX leads to a small increase in blood pressure that is prevented by l ‐citrulline supplementation or arginase deficiency, 2 measures that appear to compensate for the impact of kidney mass reduction on l ‐arginine metabolism.