Recommended Citation
Arkhipov SN, Potter DL, Sultanova RF, Ilatovskaya DV, Harris PC, and Pavlov TS. Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease. Physiol Rep 2023; 11(7):e15652.
Document Type
Article
Publication Date
4-1-2023
Publication Title
Physiol Rep
Abstract
Development of autosomal dominant polycystic kidney disease (ADPKD) involves renal epithelial cell abnormalities. Cystic fluid contains a high level of ATP that, among other effects, leads to a reduced reabsorption of electrolytes in cyst-lining cells, and thus results in cystic fluid accumulation. Earlier, we demonstrated that Pkd1(RC/RC) mice, a hypomorphic model of ADPKD, exhibit increased expression of pannexin-1, a membrane channel capable of ATP release. In the current study, we found that human ADPKD cystic epithelia have higher pannexin-1 abundance than normal collecting ducts. We hypothesized that inhibition of pannexin-1 function with probenecid can be used to attenuate ADPKD development. Renal function in male and female Pkd1(RC/RC) and control mice was monitored between 9 and 20 months of age. To test the therapeutic effects of probenecid (a uricosuric agent and a pannexin-1 blocker), osmotic minipumps were implanted in male and female Pkd1(RC/RC) mice, and probenecid or vehicle was administered for 42 days until 1 year of age. Probenecid treatment improved glomerular filtration rates and slowed renal cyst formation in male mice (as shown in histopathology). The mechanistic effects of probenecid on sodium reabsorption and fluid transport were tested on polarized mpkCCD(cl4) cells subjected to short-circuit current measurements, and in 3D cysts grown in Matrigel. In the mpkCCD(cl4) epithelial cell line, probenecid elicited higher ENaC currents and attenuated in vitro cyst formation, indicating lower sodium and less fluid retention in the cysts. Our studies open new avenues of research into targeting pannexin-1 in ADPKD pathology.
Medical Subject Headings
Mice; Male; Female; Humans; Animals; Polycystic Kidney, Autosomal Dominant; Probenecid; Disease Models, Animal; Kidney; Disease Progression; Adenosine Triphosphate; Cysts; TRPP Cation Channels
PubMed ID
37024297
Volume
11
Issue
7
First Page
15652
Last Page
15652
