Probenecid Inhibits Cyst Development in Pkd1<sup>RC/RC</sup> Mice
October 22, 2020 | 10:00 AM - 12:00 PM
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Probenecid Inhibits Cyst Development in Pkd1RC/RC Mice
- Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
- 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
Sergey N. Arkhipov,
Regina F. Sultanova,
Tengis S. Pavlov,
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.
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.
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.
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
- Private Foundation Support