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 vasopressin 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), autosomal 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 phenotype. 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 polycystic 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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Seminars in NephrologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Autosomal dominant polycystic kidney disease.Lancet. 2007; 369: 1287-1301
- Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary statement of a First National Institutes of Health/Office of Rare Diseases conference.J Pediatr. 2006; 149: 159-164
- Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat.Hum Mol Genet. 1995; 4: 575-582
- The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.Nat Genet. 1995; 10: 151-160
- Polycystic kidney disease: the complete structure of the PKD1 gene and its protein.Cell. 1995; 81: 289-298
- PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.Science. 1996; 272: 1339-1342
- PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats.Am J Hum Genet. 2002; 70: 1305-1317
- The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.Nat Genet. 2002; 30: 259-269
- A novel gene encoding a TIG multiple domain protein is a positional candidate for autosomal recessive polycystic kidney disease.Genomics. 2002; 80: 96-104
- PKD1 interacts with PKD2 through a probable coiled-coil domain.Nat Genet. 1997; 16: 179-183
- Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.Proc Natl Acad Sci U S A. 1997; 94: 6965-6970
- Fibrocystin/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia.Mol Cell Biol. 2007; 27: 3241-3252
- The versatile nature of the calcium-permeable cation channel TRPP2.EMBO Rep. 2006; 7: 787-793
- Autosomal dominant polycystic kidney disease and inherited cystic disease.in: Alpern R.J. Hebert S.C. The kidney. 4th ed. 2007: 2283-2313
- Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases.Nat Clin Pract Nephrol. 2006; 2: 40-54
- Modification of the composition of polycystin-1 multiprotein complexes by calcium and tyrosine phosphorylation.Biochim Biophys Acta. 2000; 1535: 21-35
- Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins.J Clin Invest. 1999; 104: 1459-1468
- A polycystin-1 multiprotein complex is disrupted in polycystic kidney disease cells.Mol Biol Cell. 2004; 15: 1334-1346
- Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus.J Clin Invest. 2004; 114: 1433-1443
- Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease.Dev Cell. 2006; 10: 57-69
- Proteolytic cleavage and nuclear translocation of fibrocystin is regulated by intracellular Ca2+ and activation of protein kinase C.J Biol Chem. 2006; 281: 34357-34364
- Polyductin undergoes notch-like processing and regulated release from primary cilia.Hum Mol Genet. 2007; 16: 942-956
- Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease.Curr Biol. 2002; 12: R378-R380
- Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia.Hum Mol Genet. 2003; 12: 2703-2710
- The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia.J Am Soc Nephrol. 2002; 13: 2508-2516
- Two populations of node monocilia initiate left-right asymmetry in the mouse.Cell. 2003; 114: 61-73
- Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.Nat Genet. 2003; 33: 129-137
- Bending the MDCK cell primary cilium increases intracellular calcium.J Membr Biol. 2001; 184: 71-79
- Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2.Proc Natl Acad Sci U S A. 2007; 104: 6454-6459
- Polycystin-2 is an intracellular calcium release channel.Nat Cell Biol. 2002; 4: 191-197
- Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling.J Biol Chem. 2005; 280: 41298-41306
- Specific association of the gene product of PKD2 with the TRPC1 channel.Proc Natl Acad Sci U S A. 1999; 96: 3934-3939
- Pkd2 haploinsufficiency alters intracellular calcium in vascular smooth muscle cells.Hum Mol Genet. 2003; 12: 1875-1880
- PKHD1 gene silencing may cause cell abnormal proliferation through modulation of intracellular calcium in autosomal recessive polycystic kidney disease.J Biochem Mol Biol. 2007; 40: 467-474
- Localization of mRNAs encoding Ca2+-inhibitable adenylyl cyclases along the renal tubule.J Biol Chem. 1996; 271: 19264-19271
- Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney.Kidney Int. 1999; 55: 29-62
- The role of ERK2 docking and phosphorylation of PDE4 cAMP phosphodiesterase isoforms in mediating cross-talk between the cAMP and ERK signalling pathways.Biochem Soc Trans. 2003; 31: 1186-1190
- Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist.Nat Med. 2003; 9: 1323-1326
- Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease.Nat Med. 2004; 10: 363-364
- Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat.J Am Soc Nephrol. 2005; 16: 846-851
- Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease.Am J Kidney Dis. 1997; 30: 703-709
- Lillian Jean Kaplan International Prize for advancement in the understanding of polycystic kidney disease.Kidney Int. 2003; 64: 1157-1162
- cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells.J Am Soc Nephrol. 2000; 11: 1179-1187
- Calcium restriction allows cAMP activation of the B-Raf/ERK pathway, switching cells to a cAMP-dependent growth-stimulated phenotype.J Biol Chem. 2004; 279: 40419-40430
- Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor.Kidney Int. 2000; 57: 33-40
- The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.Proc Natl Acad Sci U S A. 2006; 103: 5466-5471
- Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease.Proc Natl Acad Sci U S A. 2007; 104: 4389-4394
- Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease.Am J Kidney Dis. 1998; 32: 976-983
- Autosomal dominant polycystic kidney disease coexisting with cystic fibrosis.J Nephrol. 2006; 19: 529-534
- The relationship between cell proliferation, Cl- secretion, and renal cyst growth: a study using CFTR inhibitors.Kidney Int. 2004; 66: 1926-1938
- Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na(+),K(+),2Cl(−) Co-transporter-dependent cystic dilation.J Am Soc Nephrol. 2006; 17: 3424-3437
- EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han:SPRD rats.Kidney Int. 2003; 64: 1573-1579
- Inhibition of ErbB2 decreases c-SRC activity and ameliorates renal and biliary cystic abnormalities in the PCK rat.J Am Soc Nephrol. 2005; 16: 225A
- Inhibition of intrahepatic bile duct dilation of the polycystic kidney rat with a novel tyrosine kinase inhibitor gefitinib.Am J Pathol. 2006; 169: 1238-1250
- Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats.Kidney Int. 2004; 66: 1766-1773
- Long lasting arrest of murine polycystic kidney disease with CDK inhibitor R-Roscovitine.Nature. 2006; 444: 949-952
- Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.J Am Soc Nephrol. 2006; 17: 1604-1614
- Inhibition in autosomal dominant polycystic kidney disease (ADPKD).J Am Soc Nephrol. 2006; 17: 778A
- Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease.J Am Soc Nephrol. 2005; 16: 46-51
- Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD).Nephrol Dial Transplant. 2006; 21: 598-604
- Vasopressin antagonists in polycystic kidney disease.Kidney Int. 2005; 68: 2405-2418
- Vasopressin V2 receptor expression along rat, mouse, and human renal epithelia with focus on TAL.Am J Physiol Renal Physiol. 2007; 293: F1166-F1177
- Regulation of cAMP production in initial and terminal inner medullary collecting ducts.Kidney Int. 1998; 54: 80-86
- Antidiuretic action of vasopressin: quantitative aspects and interaction between V1a and V2 receptor-mediated effects.Cardiovasc Res. 2001; 51: 372-390
- Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome.Hum Mol Genet. 2001; 10: 2637-2644
- Contribution of comparative fish studies to general endocrinology: structure and function of some osmoregulatory hormones.J Exp Zoolog A Comp Exp Biol. 2006; 305: 787-798
- “Avian-type” renal medullary tubule organization causes immaturity of urine-concentrating ability in neonates.Kidney Int. 2001; 60: 680-693
- Kidneys sans glomeruli.Am J Physiol Renal Physiol. 2004; 286: F811-F827
- Expansion of extracellular volume in early polycystic kidney disease.Acta Med Scand. 1986; 219: 399-405
- [The effect of hypervolemia on electrolyte level and and level of volume regulating hormones in patients with autosomal dominant polycystic kidney disease.].Pol Arch Med Wewn. 1996; 96: 329-343
- Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease.Physiol Res. 2004; 53: 629-634
- Expression of aquaporins-1 and −2 during nephrogenesis and in autosomal dominant polycystic kidney disease.Am J Physiol. 1996; 271: F169-F183
- Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease.Dev Genet. 1999; 24: 309-318
- Adaptation to sustained high plasma vasopressin in water and electrolyte homeostasis in the rat transgenic for the metallothionein-vasopressin fusion gene.J Endocrinol. 2002; 173: 23-33
- Downregulation of vasopressin V2 receptor promoter activity via V1a receptor pathway.Am J Physiol Renal Physiol. 2007; 292: F1418-F1426
- V2 receptor antagonism of DDAVP-induced release of hemostasis factors in conscious dogs.J Pharmacol Exp Ther. 1997; 282: 597-602
- Therapeutic potential of vasopressin receptor antagonists.Drugs. 2007; 67: 847-858
- Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130
- Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial.JAMA. 2007; 297: 1319-1331
- Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials.JAMA. 2007; 297: 1332-1343
- Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.N Engl J Med. 2006; 355: 2099-2112
- OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats.J Pharmacol Exp Ther. 1998; 287: 860-867
- Effectiveness of OPC-41061 on polycystic kidney disease development in Pkd2WS25/-.J Am Soc Nephrol. 2005; 16: 361A
- Efficacy of OPC-41061 in the treatment of murine nephronophthisis.J Am Soc Nephrol. 2005; 16: 138A
- Vasopressin directly regulates cyst growth in the PCK rat.J Am Soc Nephrol. 2007; 19: 102-108
- Selective ADH-induced hypertrophy of the medullary thick ascending limb in Brattleboro rats.Kidney Int. 1985; 28: 456-466
- Adaptation of the rat kidney to altered water intake and urine concentration.Pflugers Arch. 1988; 412: 42-53
- Increased water intake decreases progression of polycystic kidney disease in the PCK rat.J Am Soc Nephrol. 2006; 17: 228-235
- Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3',5'-cyclic monophosphate.Gastroenterology. 2007; 132: 1104-1116
- Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 560-569
- Segmental expression of somatostatin receptor subtypes sst(1) and sst(2) in tubules and glomeruli of human kidney.Am J Physiol Renal Physiol. 2001; 280: F457-F465
- Reversal of somatostatin inhibition of AVP-induced cAMP by pertussis toxin.Kidney Int. 1988; 33: 536-542
- Somatostatin as a modulator of distal nephron water permeability.Clin Sci (Lond). 1993; 84: 455-460
- Endothelin-1 inhibits AVP-stimulated osmotic water permeability in rat inner medullary collecting duct.Am J Physiol. 1991; 261: F951-F956
- High urine volume and low urine osmolality are risk factors for faster progression of renal disease.Am J Kidney Dis. 2003; 41: 962-971
- Effects of long-term vasopressin receptor stimulation on medullary blood flow and arterial pressure.Am J Physiol. 1998; 275: R1420-R1424
- Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycorticosterone acetate-salt hypertension.Endocrinology. 2002; 143: 2759-2766
- Chronic exposure to vasopressin upregulates ENaC and sodium transport in the rat renal collecting duct and lung.Hypertension. 2001; 38: 1143-1149
- Long-term effects of vasopressin on the subcellular localization of ENaC in the renal collecting system.Kidney Int. 2006; 69: 1024-1032
- Nitric oxide in the renal medulla protects from vasopressin-induced hypertension.Hypertension. 2000; 35: 740-745
- Endothelial dysfunction and increased carotid intima-media thickness in patients with autosomal dominant polycystic kidney disease.Am J Kidney Dis. 2004; 43: 854-860
- Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease.Kidney Int. 2003; 64: 1381-1388
- Osmoregulation of thirst and vasopressin release in severe chronic renal failure.Kidney Int. 1991; 39: 295-300
- Is the process of urinary urea concentration responsible for a high glomerular filtration rate?.J Am Soc Nephrol. 1993; 4: 1091-1103
- Vasopressin increases urinary albumin excretion in rats and humans: involvement of V2 receptors and the renin-angiotensin system.Nephrol Dial Transplant. 2003; 18: 497-506
- Effect of water intake on the progression of chronic renal failure in the 5/6 nephrectomized rat.Am J Physiol. 1990; 258: F973-F979
- Contribution of vasopressin to progression of chronic renal failure: study in Brattleboro rats.Life Sci. 1999; 65: 991-1004
- High water intake ameliorates tubulointerstitial injury in rats with subtotal nephrectomy: possible role of TGF-b.Kidney Int. 1999; 55: 1800-1810
- A phase IIB pilot study of the safety and efficacy of tolvaptan, a vasopressin V2 receptor antagonist (V2RA) in patents with ADPKD.J Am Soc Nephrol. 2005; 16: 68A
- Acute and chronic osmostasis after vassopressin V2 receptor inhibition with Tolvaptan in ADPKD.J Am Soc Nephrol. 2005; 16: 361A
- Urine aquaporin 2 and cyclic AMP responses to tolvaptan administration in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2005; 16: 361A
- Phase 2 open-label study to determine safety, tolerability and efficacy of split-dose Tolvaptan in ADPKD.Am J Physiol Renal Physiol. 2007; 293: F1166-F1177
Article info
Footnotes
Supported by the National Institutes of Health grant DK44863.
Identification
Copyright
© 2008 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
