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Kidney Week

Abstract: PO2516

Tubular Urate Controls Intracellular Lactate in the Proximal Tubule with Implications for CKD

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Woodward, Owen M., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Halperin Kuhns, Victoria L., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Lane-Harris, Allison C., University of Maryland School of Medicine, Baltimore, Maryland, United States
  • Bamberg, Krister, AstraZeneca Early CVRM Biopharmaceuticals R&D, Molndal, Sweden
Background

Alterations in cell metabolism in the proximal tubule are a recognized component in the initiation and progression of chronic kidney disease (CKD) . Previously, a mouse model of hyperuricemia revealed elevated serum urate was associated with hyperglycemia and altered expression of key mitochondrial complex I and complex IV genes in the kidney, changes implicated in human CKD. Further, a recent human trial showed that blockade of proximal tubule urate transporter, URAT1, in conjunction with urate lowering therapy, slowed the progression of CKD as defined by change in albuminuria. Here, we focused on the role of renal urate handling in controlling the intracellular levels of lactate, a key metabolite and substrate of cellular respiration. Lactate is a substrate of URAT1 (SLC22A12) moving in trans with the apical entry of urate from the renal tubule lumen. We hypothesized that increased extracellular urate would promote the secretion of lactate and lower intracellular levels.

Methods

We used cultured primary normal human cortical renal epithelial cells (NHCRE) and a new hyperuricemia mouse model, produced by the inducible inactivation of the uricase gene, Uox, to explore the relationship between urate and CKD.

Results

In NHCRE cells we found that increasing the extracellular urate to 500μM significantly lowered intracellular lactate with high (4.5g/l) or reduced levels of glucose (1g/l) in the culture media, and that additional extracellular lactate could rescue intracellular levels. Further, the application of probenecid, a general anion transporter blocker with affinity for URAT1 abolishes the effects of extracellular urate on lactate levels, though probenecid alone has no effect. Finally, we sought to confirm the mechanistic connection between urate and lactate handling in the mammalian nephron. In the inducible Uox knockout hyperuricemia mouse model we found the increased plasma urate and resulting increased urinary urate excretion was associated with an increased urinary lactate excretion as well as a significant increase in the fractional excretion of lactate.

Conclusion

We conclude that increased tubular urate alters intracellular lactate levels, which potentially alters cellular respiration in the proximal tubule and affects kidney disease progression.

Funding

  • NIDDK Support