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      Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

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          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.

          Abstract

          Lewis polycystic kidney rats were treated with pyrrolidine dithiocarbamate (PDTC) from weeks 4 to 11. Quantitative analysis of serial magnetic resonance images indicated that over time, the change in total kidney volume was 1.3‐fold higher in PDTC‐treated than in vehicle‐treated rats. PDTC treatment also decreased kidney weight to body weight ratio, renal cystic volume, and proteinuria.

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          PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.

          T Mochizuki, G. Wu, T. Hayashi … (1996)
          A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.
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            Polycystic kidney disease.

            Peter Harris, Vicente Torres (2009)
            A number of inherited disorders result in renal cyst development. The most common form, autosomal dominant polycystic kidney disease (ADPKD), is a disorder most often diagnosed in adults and caused by mutation in PKD1 or PKD2. The PKD1 protein, polycystin-1, is a large receptor-like protein, whereas polycystin-2 is a transient receptor potential channel. The polycystin complex localizes to primary cilia and may act as a mechanosensor essential for maintaining the differentiated state of epithelia lining tubules in the kidney and biliary tract. Elucidation of defective cellular processes has highlighted potential therapies, some of which are now being tested in clinical trials. ARPKD is the neonatal form of PKD and is associated with enlarged kidneys and biliary dysgenesis. The disease phenotype is highly variable, ranging from neonatal death to later presentation with minimal kidney disease. ARPKD is caused by mutation in PKHD1, and two truncating mutations are associated with neonatal lethality. The ARPKD protein, fibrocystin, is localized to cilia/basal body and complexes with polycystin-2. Rare, syndromic forms of PKD also include defects of the eye, central nervous system, digits, and/or neural tube and highlight the role of cilia and pathways such as Wnt and Hh in their pathogenesis.
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              Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells

              P. A. Baeuerle, W Dröge, R Schreck … (1992)
              Dithiocarbamates and iron chelators were recently considered for the treatment of AIDS and neurodegenerative diseases. In this study, we show that dithiocarbamates and metal chelators can potently block the activation of nuclear factor kappa B (NF-kappa B), a transcription factor involved in human immunodeficiency virus type 1 (HIV-1) expression, signaling, and immediate early gene activation during inflammatory processes. Using cell cultures, the pyrrolidine derivative of dithiocarbamate (PDTC) was investigated in detail. Micromolar amounts of PDTC reversibly suppressed the release of the inhibitory subunit I kappa B from the latent cytoplasmic form of NF-kappa B in cells treated with phorbol ester, interleukin 1, and tumor necrosis factor alpha. Other DNA binding activities and the induction of AP-1 by phorbol ester were not affected. The antioxidant PDTC also blocked the activation of NF-kappa B by bacterial lipopolysaccharide (LPS), suggesting a role of oxygen radicals in the intracellular signaling of LPS. This idea was supported by demonstrating that treatment of pre-B and B cells with LPS induced the production of O2- and H2O2. PDTC prevented specifically the kappa B-dependent transactivation of reporter genes under the control of the HIV-1 long terminal repeat and simian virus 40 enhancer. The results from this study lend further support to the idea that oxygen radicals play an important role in the activation of NF-kappa B and HIV-1.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Physiol Rep
                Journal ID (iso-abbrev): Physiol Rep
                Journal ID (hwp): physreports
                Journal ID (publisher-id): phy2
                Title: Physiological Reports
                Publisher: Wiley Periodicals, Inc.
                ISSN (Electronic): 2051-817X
                Publication date Collection: December 2014
                Publication date (Electronic): 11 December 2014
                Volume: 2
                Issue: 12
                Electronic Location Identifier: e12196
                Affiliations
                [1 ]Michael Stern Laboratory for Polycystic Kidney Disease, Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
                [2 ]Brain Dynamics Centre, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia
                [3 ]Department of Radiology, Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia
                Author notes
                CorrespondenceMichelle H. T. Ta, Westmead Millennium Institute for Medical Research, Level 5, Centre for Transplant and Renal Research, 176 Hawkesbury Road (PO Box 476), Westmead, NSW 2145, Australia. Tel: +612 9845 6962 Fax: +612 9633 9351 E‐mail: michelle.ta@ 123456sydney.edu.au
                Article
                Publisher ID: phy212196
                DOI: 10.14814/phy2.12196
                PMC ID: 4332200
                PubMed ID: 25501440
                SO-VID: f4bdf79a-c85c-463c-be13-052c5730176e
                Copyright © © 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 12 May 2014
                Date revision received : 01 October 2014
                Date accepted : 13 October 2014
                Categories
                Subject: Original Research

                Keywords: bortezomib,inflammation,nuclear factor‐κb,polycystic kidney disease,pyrrolidine dithiocarbamate
                Data availability:
                Keywords: bortezomib, inflammation, nuclear factor‐κb, polycystic kidney disease, pyrrolidine dithiocarbamate

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