Anti-oxidative and immunoregulatory functions of uric acid in chronic kidney disease

• Applicant: Dr. Stefanie Steiger
• Subject Area: Nephrology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466036526

Uric acid (UA) is a metabolic breakdown product of purine nucleotides excreted via the kidneys. Most mammals including rodents use the hepatic enzyme uricase (Uox gene) to degrade UA into the more water-soluble allantoin, while birds and reptiles excrete UA mainly in the form of crystals by a complicated high energy-demanding process that allows water conservation. Humans and higher primates lack uricase activity, thus UA is the end product of the purine degradation process. As a consequence, serum UA levels are higher in humans in comparison to other mammals. The evolutionary reason underlying why humans lost uricase activity, with associated increased UA levels, is unclear. A series of potential physiological benefits of enhanced UA levels have been postulated including its anti-oxidant capacity, neuroprotective activity, a reduced incidence of age-specific cancer, and the capacity of UA to increase blood pressure in a point in the evolution of primates, where this was beneficial for up-right walking. Enhanced UA levels are mainly known for their harmful effects in the pathogenesis of diseases such as gouty arthritis, acute and chronic urate nephropathy, urolithiasis and kidney stone disease. Recently, epidemiological studies have documented robust associations between hyperuricemia (HU) and metabolic syndrome, obesity, cardiovascular disease and chronic kidney disease (CKD). However, to date causality in these contexts has not been established. Whether UA can exhibit properties, including anti-inflammatory, anti-oxidative, immunoregulatory and vasoactive effects in the context of CKD with its complications, e.g. crystalluria, diabetes, sterile inflammation and infection, is currently unknown. Thus, the aim of this research proposal is to better characterize the immunorgulatory effects of UA in CKD during sterile inflammation and infection, and the vasoactive properties of HU in CKD plus diabetes using a translational research approach with in vitro cell culture, in vivo animal experiments and patient cohort study.

• DFG Programme: Research Grants