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Kidney Week

Abstract: TH-PO408

The Effect of Lowering Uric Acid with a Xanthine Oxidase Inhibitor on PKD in Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Chaudhary, Anjana, Univ of Colorado, Aurora, Colorado, United States
  • He, Zhibin, Univ of Colorado, Aurora, Colorado, United States
  • Atwood, Daniel, Univ of Colorado, Aurora, Colorado, United States
  • Davidoff, Allen, Univ of Colorado, Aurora, Colorado, United States
  • Edelstein, Charles L., Univ of Colorado, Aurora, Colorado, United States
Background

In rodents uricase converts uric acid (UA) to allantoin and uricase inhibition with oxonic acid (OXO) raises serum UA. The aim of the study was to determine the effects of lowering UA with the xanthine oxidase inhibitor, oxypurinol (Oxy), in a mouse model of PKD.

Methods

Pkd1RC/RC (RC) mice, a hypomorphic Pkd1 gene model. OXO (300 mg/kg) or Oxy (24 mg/kg) +L-arginine (increases solubility of Oxy) treatment from day 50 to 120 of age. UA measured by LC/MS-MS. Males+females analyzed together. Caspase-1 protein measured by immunoblot. Cyst index (% of kidney cystic) cyst number and cyst area determined on cross sections by a computerized algorithm.

Results

See Table. Pharmacokinetic studies in normal rodents showed a 5 -fold increase in serum UA 2 hrs after OXO dosing. Oxy did not affect PKD in mice likely because baseline UA levels were low in rodents (0.35 mg/dL) due to uricase. So, the effect of OXO that increases UA in mice was determined. In RC mice, OXO resulted in a significant increase in serum UA, 2 kidney/body weight ratio (2K/BW) (%) and cyst indices. Mechanisms of increased PKD caused by UA were investigated: OXO resulted in a 50% increase in serum UA and an increase in pro-inflammatory cytokines/chemokines in the kidney: IL-5, IL-6, CXCL1. On polarized light UA crystals were not seen and caspase-1, a marker of the inflammasome, was not increased in OXO-treated kidneys. Oxy resulted in a 300% decrease in serum UA and significantly decreased the increase in 2K/BW and cyst indices caused by increasing UA with OXO.

Conclusion

Increasing serum UA by inhibiting uricase with OXO results in an increase in kidney weight and cyst indices. The combination of OXO + Oxy decreased the increase in kidney weight and cyst indices induced by OXO. A potential mechanisms of how OXO causes increased cyst growth in RC mice is induction of a pro-inflammatory cytokine storm in the PKD kidney in the absence of UA crystalluria or inflammasome activation.

 VehOxyVehOXOOXOOXO+Oxy
2K/BW(%)2.12.21.82.1*2.011.77*
Cyst index (%)9.510610*1410.8*
Cyst No124150134185*9574
Cyst size μm26990625164216442104917440*
Caspase-1/GAPDH  0.60.60.70.7
IL-5/IL-6/CXCL1 (pg/mL)  0.1/3.4/120.3/10.7/19 All=*  

*P<0.05. RDU=relative densitometry units, N=8-16 per group

Funding

  • Commercial Support – XORTX Pharmaceuticals