Vasopressin Antagonists in Polycystic Kidney ... Vasopressin Antagonists in Polycystic Kidney Disease

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    Vasopressin Antagonists in Polycystic Kidney Disease

    Vicente E. Torres, MD

    Summary: Increased cell proliferation and fluid secretion, probably driven by alterations in intracellular calcium homeostasis and cyclic adenosine 3,5-phosphate, play an important role in the development and progression of polycystic kidney disease. Hormone receptors that affect cyclic adenosine monophosphate and are preferentially expressed in affected tissues are logical treatment targets. There is a sound rationale for considering the arginine vaso- pressin V2 receptor as a target. The arginine vasopressin V2 receptor antagonists OPC-31260 and tolvaptan inhibit the development of polycystic kidney disease in cpk mice and in three animal orthologs to human autosomal recessive polycystic kidney disease (PCK rat), autoso- mal dominant polycystic kidney disease (Pkd2/WS25 mice), and nephronophthisis (pcy mouse). PCK rats that are homozygous for an arginine vasopressin mutation and lack circulating vasopressin are markedly protected. Administration of V2 receptor agonist 1-deamino-8-D-arginine vasopressin to these animals completely recovers the cystic pheno- type. Administration of 1-deamino-8-D-arginine vasopressin to PCK rats with normal arginine vasopressin aggravates the disease. Suppression of arginine vasopressin release by high water intake is protective. V2 receptor antagonists may have additional beneficial effects on hypertension and chronic kidney disease progression. A number of clinical studies in poly- cystic kidney disease have been performed or are currently active. The results of phase 2 and phase 2-3 clinical trials suggest that tolvaptan is safe and well tolerated in autosomal dominant polycystic kidney disease. A phase 3, placebo-controlled, double-blind study in 18- to 50-yr-old patients with autosomal dominant polycystic kidney disease and preserved renal function but relatively rapid progression, as indicated by a total kidney volume �750 ml, has been initiated and will determine whether tolvaptan is effective in slowing down the progression of this disease. Semin Nephrol 28:306-317 © 2008 Elsevier Inc. All rights reserved. Keywords: Autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, nephronophthisis, vasopressin, vasopressin V2 receptor antagonist

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    utosomal-dominant polycystic kidney disease (ADPKD) is the most common of the inherited renal cystic diseases and a

    eading cause of end-stage renal disease.1 It is enetically heterogeneous with 2 genes identi- ed: PKD1 and PKD2. Autosomal-recessive olycystic kidney disease (ARPKD) is less com- on than ADPKD, but together with nephroph-

    hisis is the leading cause of end-stage renal

    ivision of Nephrology, Mayo Clinic College of Medicine, Rochester, MN upported by the National Institutes of Health grant DK44863. ddress reprint requests to Vicente E. Torres, MD, Division of Nephrology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail:

    270-9295/08/$ - see front matter

    s2008 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2008.03.003


    isease in childhood. It is caused by mutations o PKHD1.2 Currently there is no effective ther- py for these diseases. Advances in the under- tanding of cystogenesis and availability of ge- etically related animal models provide unique pportunities to develop effective treatments. his article summarizes recent advances, rais-

    ng the hope that vasopressin V2-receptor an- agonists will become a safe and effective ther- py for PKD.


    he cloning of PKD1 and PKD2 in 1994 and 9963–6 and of PKHD1 in 20027–9 were major

    teps toward the understanding of PKD. The

    rs in Nephrology, Vol 28, No 3, May 2008, pp 306-317

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    Vasopressin antagonists in PKD 307

    roteins encoded by these genes are mem- rane-associated proteins. Polycystin-2 (PC2 or RPP2), the protein encoded by PKD2, is a TRP hannel with high permeability to calcium. olycystin-1 (PC1) and fibrocystin/polyductin FC/PD) are thought to be cell surface recep- ors that directly in the case of PC110,11 or indi- ectly in the case of FC/PD12 interact with and egulate the channel function of PC2. PC1 and C/PD also have other functions, some of hich are in turn regulated by PC2. For exam- le, PC2 binding to PC1 reduces the ability of C1 to constitutively activate G proteins.13

    PCs and FC/PD are multifunctional proteins ith numerous interacting partners that are es-

    ential to maintain the differentiated phenotype f the tubular epithelium.14 Reduction in one of hese proteins below a critical level induces hanges in protein trafficking and targeting, ell-matrix and cell-cell interactions, prolifera- ion and apoptosis, planar polarity, and fluid ecretion that result in the initiation and growth f cysts.15 The underlying molecular mecha- isms are complex. The PCs and FC/PD partic-

    pate in kinase cascades that connect interac- ions at cell-matrix and cell-cell contacts to the egulation of nuclear transcription and cell dif- erentiation.16–18 PC1 and FC/PD also may un- ergo regulated intramembrane proteolysis, a rocess initiated by ligand binding that releases ytoplasmic peptide fragments that migrate to he nucleus and affect transcription.19–22

    The role of the PKD proteins in primary cilia nd regulation of intracellular calcium homeosta- is has received the most attention. PC1, PC2, and C/PD are located in primary cilia.23–25 In the rimary cilia, the PC/FC complex senses and ranslates mechanical stimulation into calcium en- ry, which triggers calcium-induced calcium re- ease from the endoplasmic reticulum.26–28 PC2 lso is present in the endoplasmic reticulum, here it interacts with other calcium channels,

    he IP3R and RR.29–32 Together, PC2, inositol riphosphate (IP3R), and ryanodine receptor RR) are responsible for calcium release from ntracellular stores. Reductions in the levels of Cs or FC/PD below a critical threshold impair

    ntracellular calcium homeostasis.33,34 In renal ubular epithelial cells, intracellular calcium

    imits cyclic adenosine monophosphate (cAMP) w

    ccumulation by inhibiting AC6 and stimulating hosphodiesterase-1.35–37 This may account for he renal accumulation of cAMP in animal mod- ls of ADPKD and ARPKD.38–41 cAMP stimu- ates cell proliferation and chloride (cystic fi- rosis transmembrane conductance regulator– ediated)-driven fluid secretion.42–44 Athough

    nder normal conditions cAMP inhibits mito- en-activated protein kinase (MAPK) signaling nd cell proliferation, in conditions of calcium eprivation such as in PKD it stimulates cell roliferation in an src-, ras-, and b-raf–depen- ent manner. This proliferative effect may be nhanced further by the stimulation of mislo- alized Erb-B receptors by epidermal growth actor-like factors present in cyst fluid.45 The ignaling pathways activated downstream from utated PC1 converge with those activated in

    uberous sclerosis complex, possibly owing to isruption of the physical interaction between C1 and tuberin or to phosphorylation of tu- erin by ERK and Akt, leading to activation of ammalian target of rapamycin.46


    he increased understanding of the molecular echanisms of PKD has provided a number of

    argets for therapeutic intervention (Fig. 1). riptolide binds to PC2, induces calcium re-

    ease by a PC2-dependent mechanism, and ame- iorates cystic disease in a Pkd1 animal model.47

    onsistent with observations of milder disease n patients who have ADPKD and cystic fibro- is,48,49 cystic fibrosis transmembrane conduc- ance regulator inhibitors inhibit the develop- ent of cysts by Madin-Darby canine kidney

    MDCK) cells in collagen gels50 and in meta- ephric organ cultures51 by inhibiting chloride ecretion. How to apply this strategy without nducing cystic fibrosis will be challenging. rb-B tyrosine kinase inhibitors have been used uccessfully in a variety of models, but different rb-B receptors seem to be important in differ- nt animal models.45,52–55 These drugs have sig- ificant toxicity, which may limit their use for xtended periods of time. The same can be said or src, mek, and cdk inhibitors.56–58 This con- ern is less for mammalian target of rapamycin nhibitors thanks to the extensive experience

    ith this drug in transplantation.46,59,60

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    308 V.E. Torres

    ATIONALE FOR HERAPIES TARGETING HE ARGININE VASOPRESSIN– 2–RECEPTOR AXIS AND RENAL CAMP argeting strategies that minimize the effects of medication on normal cells are essential in

    hronic diseases that require long-term treat- ents. The central role of cAMP in the patho-

    enesis of PKD and the ability to hormonally odulate cAMP in a cell-specific manner pro-

    igure 1. Diagram depicting hypothetical pathways reatment with triptolide, cystic fibrosis transmembrane xtracellularly regulated kinase (ERK) or cyclin-dependen omatostatin, and V2-receptor antagonists. Dysregulatio zation of ErbB receptors occur in cells/kidneys bearing P idneys may result from: (1) disruption of the polycys eceptor; (2) stimulation of Ca2� inhibitable AC6 and Ca2�]i; (3) increased levels of circulating vasopressin ow f vasopres