Background: Unconjugated
bilirubin (UCB) is more than the final product of
heme catabolism. Mildly elevated systemic
bilirubin concentrations, such as in
Gilbert syndrome (GS), protect against various oxidative stress-mediated and
metabolic diseases, including
cardiovascular disease,
type 2 diabetes mellitus,
metabolic syndrome,
cancer, and age-related disease. The Gunn rat is an animal model of
hereditary hyperbilirubinemia widely used in assessing the effect of high serum
bilirubin concentration in various organs. The present work aims to understand if life-long
hyperbilirubinemia and
bilirubin-priming might contribute to protection against
atherosclerosis and
diabetic nephropathy (DN) at the cellular level. Methods: Primary aortic endothelial cells and podocytes obtained from hyperbilirubinemic homozygous jj and normobilirubinemic heterozygous Nj Gunn rats were exposed to
Palmitic Acid (PA) and
Angiotensin II (Ang II), respectively, and the effects on cell viability and the activation of damage-related metabolic pathways evaluated. Results were validated on immortalized H5V and HK2 cells exposed to damage after UCB pretreatment. Results: In both primary cell models, cells obtained from jj Gunn rats showed as significantly higher than Nj Gunn rats at any dose of the toxic agent. Reduction in CHOP expression and
IL-6 release was observed in jj primary aortic endothelial cells exposed to PA compared to Nj cells. The same occurred on H5V pretreated with Unconjugated
bilirubin. Upon Ang II treatment, primary podocytes from jj Gunn rats showed lower DNA fragmentation, cleaved
caspase-3, and cleaved PARP induction than primary podocytes from Nj Gunn rats. In HK2 cells, the induction by Ang II of HIF-1α and LOXl2 was significantly reduced by UCB pretreatment. Conclusion: Our data suggest that in models of
atherosclerosis and DN life-long
hyperbilirubinemia exposure or
bilirubin-priming significantly contribute to decrease the injury by enhancing thecellular defensive response.