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 enzyme uricase (Uox gene) to degrade UA into the more water-soluble allantoin, while humans and higher primates lack uricase activity. Therefore, UA is the end product of the purine degradation process. As a consequence, serum UA levels are relatively high in humans in comparison to other mammals. The evolutionary reason why humans lost uricase activity is not clear. 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 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, causality in these contexts has not been established. Published in vitro and in vivo data on the functional role of soluble UA (sUA) are discrepant. We recently showed that a crystal-free sUA preparation (with NaOH) elicits anti-inflammatory effects in activated monocytes from healthy individuals through a process mediated by the intracellular uptake of sUA via the urate transporter SLC2A9/GLUT9. This is consistent with monocytes from hyperuricemic CKD patients that were found to be less responsive to inflammatory stimuli as compared to monocytes from healthy individuals. Moreover, Alb-creERT2;Glut9lox/lox mice with HU (serum UA of 9-11 mg/dl) showed a suppressed immune response in gouty arthritis-like sterile inflammation compared with Glut9lox/lox control mice without HU, a process that was more pronounced in mice with HU and CKD. Thus, these findings suggest that HU acts as an intrinsic suppressor of innate immunity where sUA modulates the capacity of monocytes to respond to danger signals. Whether UA may act not only anti-inflammatory but also anti-oxidative and immunoregulatory in the context of CKD with its complications, such as UA crystalluria, diabetes, sterile inflammation and infection, is currently unknown. Thus, the aim of this research proposal is to better characterize the pathomechanisms of UA during sterile inflammation and host defense in CKD by using innovative research tools including animal models as well as a translational research approach with patient cohorts. We expect that specific targeting of UA may allow more specific impacts compared to targeting xanthine oxidase, especially in regard to the opposite roles of UA and ROS in sterile inflammation and host defense.

• DFG Programme: Research Grants