Asymptomatic Hyperuricemia Promotes Recovery from Ischemic Organ Injury by Modulating the Phenotype of Macrophages.

Paola Romagnani,Hans-Joachim Anders,Qiuyue Ma,Stefanie Steiger,Mireia Molina-Van den Bosch,Viviane Gnemmi,Chenyu Li,Qiubo Li,Giulia Carangelo,Letizia De Chiara

doi:10.3390/cells11040626

Abstract

Acute organ injury, such as acute kidney injury (AKI) and disease (AKD), are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function but the impact of asymptomatic HU on the different phases of AKI/AKD is incompletely understood. We hypothesized that asymptomatic HU would attenuate AKD because soluble, in contrast to crystalline, uric acid (sUA) can attenuate sterile inflammation. In vitro, 10 mg/dL sUA decreased reactive oxygen species and interleukin-6 production in macrophages, while enhancing fatty acid oxidation as compared with a physiological concentration of 5 mg/dL sUA or medium. In transgenic mice, asymptomatic HU of 7–10 mg/dL did not affect post-ischemic AKI/AKD but accelerated the recovery of kidney excretory function on day 14. Improved functional outcome was associated with better tubular integrity, less peritubular inflammation, and interstitial fibrosis. Mechanistic studies suggested that HU shifted macrophage polarization towards an anti-inflammatory M2-like phenotype characterized by expression of anti-oxidative and metabolic genes as compared with post-ischemic AKI-chronic kidney disease transition in mice without HU. Our data imply that asymptomatic HU acts as anti-oxidant on macrophages and tubular epithelial cells, which endorses the recovery of kidney function and structure upon AKI.

Highlights

Acute kidney injury (AKI) and disease (AKD) are serious common public health concerns with high incidence, mortality, morbidity, and economic impact [1]
The UA concentrations in the supernatants after stimulation correlated with the sUA concentrations of 5 and 10 mg/dL added to the macrophage culture (Figure S1B)
Stimulating macrophages with LPS induced an increase in the production of reactive oxygen species (ROS), as indicated by the fluorescence signal of dihydrorhodamine 123 as compared with medium, an effect that was reduced in the presence of 10 mg/dL sUA

Summary

Introduction

Acute kidney injury (AKI) and disease (AKD) are serious common public health concerns with high incidence, mortality, morbidity, and economic impact [1]. Triggers of AKI/AKD are diverse and include ischemia, sepsis, and toxic injuries [2]. AKI/AKD survivors experience irreversible losses of more or less epithelial cells and entire nephrons, which implies chronic kidney disease (CKD) with all its implications on cardiovascular health, kidney cancer, and the risk for ultimate kidney failure [2]. Independent of the primary cause, AKI/AKD is characterized by tubular epithelial cell injury and immune cell infiltration [3]. Previous reports demonstrate an essential role for macrophages on tubular epithelial cell survival and recovery in AKI/AKD, both during the injury as well as the repair and/or tissue remodeling phase [4,5].

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