Open AccessPyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease
Author(s) -
Ta Michelle H. T.,
Rao Padmashree,
Korgaonkar Mayuresh,
Foster Sheryl F.,
Peduto Anthony,
Harris David C. H.,
Rangan Gopala K.
Publication year - 2014
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12196
Subject(s) - pyrrolidine dithiocarbamate , polycystic kidney disease , endocrinology , kidney , kidney disease , medicine , inflammation , nf κb
Heterocyclic dithiocarbamates have anti‐inflammatory and anti‐proliferative effects in rodent models of chronic kidney disease. In this study, we tested the hypothesis that pyrrolidine dithiocarbamate ( PDTC ) reduces the progression of polycystic kidney disease ( PKD ). Male Lewis polycystic kidney ( LPK ) rats (an ortholog of Nek8/ NPHP 9 ) received intraperitoneal injections of either saline vehicle or PDTC (40 mg/kg once or twice daily) from postnatal weeks 4 until 11. By serial magnetic resonance imaging at weeks 5 and 10, the relative within‐rat increase in total kidney volume and cyst volume were 1.3‐fold ( P = 0.01) and 1.4‐fold ( P < 0.01) greater, respectively, in LPK + Vehicle compared to the LPK + PDTC (40 mg/kg twice daily) group. At week 11 in LPK rats, PDTC attenuated the increase in kidney weight to body weight ratio by 25% ( P < 0.01) and proteinuria by 66% ( P < 0.05 vs. LPK + Vehicle) but did not improve renal dysfunction. By quantitative whole‐slide image analysis, PDTC did not alter interstitial CD 68+ cell accumulation, interstitial fibrosis, or renal cell proliferation in LPK rats at week 11. The phosphorylated form of the nuclear factor ( NF )‐ κ B subunit, p105, was increased in cystic epithelial cells of LPK rats, but was not altered by PDTC . Moreover, PDTC did not significantly alter nuclear expression of the p50 subunit or NF ‐ κ B (p65)‐ DNA binding. Kidney enlargement in LPK rats was resistant to chronic treatment with a proteasome inhibitor, bortezomib. In conclusion, PDTC reduced renal cystic enlargement and proteinuria but lacked anti‐inflammatory effects in LPK rats.