L-Citrulline Attenuates Multisystem Oxidative Stress in a Preterm Model of Postnatal Undernutrition

Background and aim: Extremely low gestational age neonates (ELGANs) born < 26 weeks of gestation often have postnatal growth failure from suboptimal nutrition and chronic extrauterine stressors; undernutrition induces inflammation and oxidative stress (OS) and the risk for acute and chronic lung and kidney diseases. Preclinical and clinical studies suggest that OS and inflammation have a synergistic relationship in which each amplifies the other. We have previously reported in newborn rats that undernutrition for the first 21 days after birth induces growth failure, systemic and local inflammation, and histopathological changes in several organs that were mitigated by concurrent treatment with L-citrulline. L-citrulline is an amino acid that is well tolerated by ELGANS. It reduces inflammation by decreasing activation of Nuclear factor-κB (NFkB), and OS by maintaining coupling of nitric oxide synthase. This study aims to investigate whether L-citrulline reduces OS markers and improves histopathology in the lungs and kidneys of a neonatal model of postnatal undernutrition. Methods: Neonatal Sprague Dawley rat pups were assigned to two groups: normal nutrition (litter size n = 10) and undernutrition (litter size n = 18) by adjusting the nursing dam’s litter size. Body weight was recorded daily, and both groups received intraperitoneal injections of either saline or L-citrulline (2.5 g/kg) every day for 21 days. On postnatal day 21, lung and kidney tissues were collected for histological evaluation using H&E and pentachrome staining, and mRNA and protein analyses. The Thiobarbituric Acid Reactive Substances (TBARS) assay was used to detect a biomarker of oxidative stress, malondialdehyde (MDA). Results: In the lungs, undernourished animals had a higher MDA concentration, which was decreased in the undernourished animals receiving concurrent L-citrulline (n=4; p< 0.001). The protein expression of SOD1, 2, and 3 was higher in the lungs of undernourished animals compared to those treated with L-citrulline (n=4; p< 0.05). Undernourished animals treated with L-citrulline also had reduced immune cell infiltration in the lungs compared to the undernourished animals receiving saline (n=4; p< 0.001). In the kidneys, undernourished animals had significantly higher MDA levels than controls (n=4; p< 0.001). SOD1 and SOD2 protein expression was also increased in the kidneys of undernourished animals. L-citrulline supplementation in undernourished animals significantly decreased SOD protein expression (n=4; p< 0.005) Conclusion: Concurrent L-citrulline supplementation can improve OS and inflammation associated with postnatal undernutrition in the lungs and kidneys of undernourished animals. L-citrulline is safe and well-tolerated in premature infants. Our data suggest that L-Citrulline may protect developing organs from OS, potentially decreasing acute and chronic diseases in ELGANs with postnatal growth failure This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.