Source of hyperuricemia drives significantly divergent transcriptional alterations in the kidney
Victoria L Halperin Kuhns, Allison C Lane-Harris, Owen M Woodward
University Of Maryland School Of Medicine, Baltimore
Objective: Compare underexcretion (UX) vs overproduction (OP) types of hyperuricemia (HUA), and how each type affects renal transcriptional profiles to provide insight into how HUA may impact kidney disease.
Background: HUA contributes to the development of gout, kidney stones, and kidney disease. Many studies exploring the effects of HUA on renal disease progression have yielded inconsistent results based on assumptions that all types of HUA have the same pathophysiological outcomes. UX type and OP type HUA result in similar serum urate levels, but critically important differences in renal urate handling resulting in disparate tubular urate levels. We compared transcriptional profiles of kidneys of two functionally different mouse models of HUA. Our established UX mouse model (abcg2-q140k) has decreased urate secretion, leading to increased serum urate in male mice only. The OP model is a novel inducible knock-out of the urate metabolizing gene uricase (uox-iko), which renders mice unable to metabolize urate, increasing circulating urate levels and urinary urate excretion (uue).
Methods: Uox-iko male mice were induced at 9 weeks of age. Mice had elevated serum urate levels similar to age matched abcg2-q140k male mice from 2 weeks to 6 months after induction. Rna-seq was performed on kidneys harvested from HUA male animals from both models and appropriate controls, followed by deseq2 differential expression analysis, and pathway analyses (david bioinformatics resource 6.8, string database v11.5).
Findings: Uox-iko mice had increased overall uue and increased fractional excretion of urate (FEUA), implying higher tubular urate, consistent with urate OP. These mice had visibly cloudy urine, due to urate crystal precipitation. In contrast, abcg2-q140k mice showed no change in overall uue, with decreased FEUA, implying lower tubular urate, consistent with urate UX. The two models of HUA showed dramatically divergent transcription profiles. Abcg2-q140k mice had 486 differentially expressed genes (degs, bh adjusted p < 0.05), while the uox-iko mice had only 52 degs. Only 2 degs were seen in both models, reg3g and slc16a7, implying that either the levels of tubular urate or intracellular urate of the renal epithelial cells, not the serum urate levels, must be affecting renal gene expression. Abcg2-q140k mice had 64 out of 486 degs involved in metabolic pathways, including oxidative phosphorylation, vitamin and fat digestion and absorption, indicating that increased intracellular urate may be driving changes in renal metabolism. In contrast, uox-iko degs were found in immune signaling pathways, including cytokine-cytokine receptor, chemokine, il-17, tnf, and jak-stat signaling, implying increased tubular inflammation and injury related to increased tubular urate. Other degs included renal injury associated genes lcn2, stc1, and umod, supporting microcrystal induced tubular injury. None of these genes were differentially expressed in the abcg2-q140k mice, indicating decreased secretion does not result in the same type of tubular injury.
Significance: Mice with OP HUA were more likely to develop crystals, resulting in altered immune signaling, while those with UX HUA had altered metabolic pathways, indicating the need for a more