title: Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease.
abstract: 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/NPHP9) 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 CD68+ cell accumulation, interstitial fibrosis, or renal cell proliferation in LPK rats at week 11. The phosphorylated form of the nuclear factor (NF)-κB 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-κB (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.
authors.affiliation: Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Michelle H T
authors.initials: MH
authors.lastname: Ta
authors.affiliation: Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Padmashree
authors.initials: P
authors.lastname: Rao
authors.affiliation: Brain Dynamics Centre, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Mayuresh
authors.initials: M
authors.lastname: Korgaonkar
authors.affiliation: Department of Radiology, Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Sheryl F
authors.initials: SF
authors.lastname: Foster
authors.affiliation: Department of Radiology, Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Peduto
authors.affiliation: Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: David C H
authors.initials: DC
authors.lastname: Harris
authors.affiliation: Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Gopala K
authors.initials: GK
authors.lastname: Rangan
keywords: Bortezomib; inflammation; nuclear factor‐κB; polycystic kidney disease; pyrrolidine dithiocarbamate