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Kidney Week

Abstract: PO1559

Probenecid Inhibits Cyst Development in Pkd1RC/RC Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Arkhipov, Sergey N., Henry Ford Health System, Detroit, Michigan, United States
  • Sultanova, Regina F., Medical University of South Carolina, Charleston, South Carolina, United States
  • Ilatovskaya, Daria, Medical University of South Carolina, Charleston, South Carolina, United States
  • Pavlov, Tengis S., Henry Ford Health System, Detroit, Michigan, United States
Background

ADPKD cysts contain high levels of ATP that contribute to cyst enlargement. Among other effects, ATP excess leads to a reduced reabsorption in cyst-lining cells and cyst fluid accumulation. We demonstrated that Pkd1RC/RC mice, a model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. Probenecid, a uricosuric agent, is also used as a pannexin-1 blocker reducing ATP release. We studied therapeutic potential of probenecid in Pkd1RC/RC mice and its effect on sodium reabsorption.

Methods

Pkd1RC/RC mice, a hypomorphic model of ADPKD, were aged till 10.5 months and osmotic minipumps were implanted to deliver probenecid for 42 days. After treatment, 1 year old conscious mice were subjected to glomerular filtration rate (GFR) measurements and kidneys were collected for histomorphological studies. Effect of probenecid on Na+ reabsorption was tested on mpkCCD cells seeded onto permeable supports with open-circuit current measurements.

Results

In vivo inulin clearance study demonstrates that Pkd1RC/RC mice have normal GFR 1.05±0.09 ml/min/100g at the 6 months old age (n=15) whereas GFR in C57BL/6 mice - 0.94±0.1 ml/min/100g (n=8). With disease progression GFR in Pkd1RC/RC mice reduces to 0.36±0.08 ml/min/100g at 12 months age. 42 days long probenecid treatment (15.9 mg/kg/day) significantly improves GFR to 1.43±0.11 ml/min/100g (p<0.001). Probenecid treatment also reduced kidney hypertrophy: kidney/TBW ratio in vehicle group was 2.54±0.17% vs 1.76±0.05% probenecid (p<0.05). Histological study on sectioned kidneys revealed that probenecid significantly reduces cyst size. Cyst to total slice area ratio was 13.9±2.7% (vehicle) vs 3.4±0.8% (probenecid) (n=5 each group).
Earlier we have shown that probenecid decreases luminal ATP release in immortalized CD cell culture. As ATP is cable of downregulating Na+ reabsorption via the epithelial sodium channel we tested if probenecid increases ENaC activity. We applied probenecid to mpkCCD cell monolayer and found that the drug causes a bell-shaped dose-dependent increase of amiloride-sensitive transepithelial flux with maximal effect at 50 µM.

Conclusion

Probenecid demonstrates therapeutic potential against ADPKD cyst progression in a Pkd1RC/RC mouse model by reducing cyst size, renal hypertrophy and supporting GFR and reabsorption from the cyst space. Support: ASN Carl W. Gottschalk Award

Funding

  • Private Foundation Support