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Pretreatment With Probenecid Downregulates Kidney Pendrin Expression and Potentiates Hydrochlorothiazde Diuresis in Rat
Author(s) -
Barone Sharon,
Xu Jie,
Zahedi Kamyar,
Soleimani Manoocher
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.676.3
Subject(s) - probenecid , pendrin , chemistry , diuretic , endocrinology , medicine , hydrochlorothiazide , organic anion transporter 1 , diuresis , pharmacology , kidney , reabsorption , transporter , biochemistry , blood pressure , gene
Background Concomitant deficiency of the Na‐Cl co‐transporter (NCC) and pendrin leads to significant salt wasting. Probenecid is an inhibitor of the organic anion transporters in the kidney proximal tubule and enhances uric acid excretion. Probenecid is also an inhibitor of pendrin in mammary cells (AJP Endo/Metab, 2003). The diuretic effect of Hydrochlorothiazide (HCTZ), which is a specific inhibitor of NCC, is significantly blunted consequent to compensatory salt absorption by pendrin. The downregulation or inactivation of pendrin enhances the diuretic effect of HCTZ. Hypothesis Pre‐treatment with probenecid will downregulate pendrin, therefore leaving NCC as the main salt absorbing transporter in the distal nephron. These changes enhance the diuretic effect of HCTZ. Results Male Sprague Dawley rats (200–225 gm BW) were pre‐treated with probenecid, at 250 mg/kg/day IP for 6 days. Urine output increased from 9.5 ml to 13.8 ml /24 hr on day 6 of probenecid treatment (p<0.05, n=5). Treatment of rats with HCTZ alone (40 mg/kg) for 4 days caused a mild diuresis which did not achieve statistical significance. However, treatment of rats that were pretreated with Probenecid for 6 days with a combination of Probenecid plus HCTZ for 4 additional days increased the urine output by greater than 300% to 42.1 ml/day (p<0.001, n = 5) compared to Probenecid‐treated or HCTZ‐treated animals. The animals treated with Probenecid plus HCTZ developed significant volume depletion as judged by >3 fold increase in the expression of renin in their kidneys. Immunofluorscence studies demonstrated an ~80% reduction in pendrin expression in kidneys of rats treated with Probenecid. Probenecid treatment reduced HCTZ excretion by ~40% suggesting competition between probenecid and HCTZ for secretion via organic anion transporters in the proximal tubule. The impaired excretion of HCTZ was unlikely to be responsible for the profound diuresis by probenecid plus HCTZ. Conclusion Despite being considered a mild agent, we propose that HCTZ could be a potent diuretic when administered in individuals pre‐treated with probenecid. The treatment with probenecid should also prevent the generation of hyperuricemia by HCTZ. Support or Funding Information Merit Review Award by Veterans Administration. Center on Genetics of Transport, University of Cincinnati