Vasopressin antagonists in polycystic kidney disease

Abstract

Patient 1. A 17-year-old boy with gross hematuria was referred to our center 18 years ago. He had been hit on the left flank area during a football scrimmage. His father and uncle had autosomal-dominant polycystic kidney disease (ADPKD). On examination, his height was 1.88 m; weight, 73.2 kg; and blood pressure (BP), 160/100 mm Hg. Moderate left costovertebral angle tenderness was noted. The serum creatinine was 0.9 mg/dL. Ultrasound examination disclosed kidneys of 12.8 and 12 cm with multiple cysts. No cysts appeared in the liver or pancreas. After resting for 30 minutes, the BP was 130/80 mm Hg. He returned for follow-up 1 year later. The BP was 145/92 mm Hg; enalapril, 5 mg daily, was started. Between 1988 and 1999, he was followed by his family physician and made occasional visits to our center. Fourteen years ago, he returned for a study on the accuracy and reproducibility of kidney volume measurements by electron beam computed tomography (CT). His weight was 81.6 kg and BP 138/86 mm Hg. The serum creatinine was 1.0 mg/dL. The total kidney volume was estimated to be 1120 mL Figure 1a . The dose of enalapril was increased to 10 mg daily. During the next 6 years, he remained active, working as a plumber, and was followed at home. Eight years ago, he returned with increasing systolic BPs, between 145 and 160 mm Hg. His weight was 98 kg and BP 160/90 mm Hg. Palpable polycystic kidneys and a small umbilical hernia were noted. The serum creatinine and iothalamate clearances were 1.3 mg/dL and 111 mL/min/1.73 m2. Proteinuria (urine protein/osmolality ratio of 0.28) was detected for the first time. The administration of enalapril was changed to lisinopril, 20 mg daily. Six years ago, total kidney volume was 1568 mL Figure 1b and c. Treatment with atorvastatin was initiated for hypercholesterolemia. Over the next 5 years, he was followed yearly in our center. Moderate polyuria was noted on 24-hour urine collections, averaging 3162 mL. By his account, he had always drunk lots of water. The administration of lisinopril was increased to 20 mg twice daily; candesartan was added later and increased to 16 mg daily with the goal of maintaining a systolic BP below 130 mm Hg. At the most recent visit, last year, his weight was 107 kg; BP, 120/80 mm Hg; serum creatinine, 1.1 mg/dL; iothalamate clearance, 81 mL/min/m2; urine albumin excretion, 119 mg/24 hours; and total kidney volume measured by magnetic resonance, 2217 mL Figure 1d. Figure 2 summarizes the kidney volume, serum creatinine, iothalamate clearance, and first morning urine osmolality values over 17 years of follow-up. Patient 2. A 31-year-old man was admitted to a local hospital in 1972 for acute-onset right flank pain and gross hematuria. An excretory urogram showed that the right kidney was considerably larger than the left, with a delayed nephrogram and a filling defect in the renal pelvis consistent with a clot Figure 3a and b . A right ureteral catheter was placed, and he was referred to our center. Several members of his family had died from complications of ADPKD. His height was 1.75 m; weight, 77 kg; and BP, 148/102 mm Hg. An enlarged, tender, right polycystic kidney was palpable. The gross hematuria and urinary obstruction resolved, and the serum creatinine concentration decreased from 1.8 to 1.3 mg/dL without further treatment. Hydrochlorothiazide-spironolactone was prescribed for hypertension. Between 1974 and 2003, he was followed regularly in our clinic. It was noted in the history that he had liked to drink abundant fluids since childhood. The average 24-hour urine output prior to a decline in renal function was 2330 mL. Multiple urinalyses showed trace to 1+ proteinuria. The hypertension was consistently well controlled, initially with hydrochlorothiazide-spironolactone and later with the addition of atenolol. These were later replaced with enalapril, with the subsequent addition of amlodipine and labetalol. Hyperlipidemia was controlled initially with lovastatin and later simvastatin. In 1990 and 1999 he participated in studies on the accuracy and reproducibility of renal volume measurements and longitudinal analysis of renal volume changes by electron beam CT in ADPKD Figure 3c. A follow-up CT scan also was obtained 2 years ago Figure 3d. The renal volume increased from 1975 mL in 1990 to 2704 mL in 1999 and 3728 mL in 2003. The changes in renal volume were associated with a progressive decline in iothalamate clearance and an increase in serum creatinine from 1.2 mg/dL in 1974 to 5.7 mg/dL in 2003. DR. VICENTE E. TORRES (Division of Nephrology, Mayo Clinic College of Medicine, Rochester, Minnesota): Cyst development and growth, impaired urinary concentrating capacity, hypertension, and low-grade proteinuria are often undetected manifestations of ADPKD, occurring decades before renal function starts declining. Concerns about medical insurability are an impediment to early detection and prevention of complications of this disease in the United States. Despite awareness of the increased risk associated with a family history of the disease, frequently the diagnosis is made only after an acute manifestation. The two patients presented here illustrate this point as well as the inexorable progression from early disease by 17 years of age in Patient 1 to end-stage renal failure by age 62 years in Patient 2. I would like to suggest that the development of cysts, impaired urinary concentration, hypertension, and low-grade proteinuria during this silent phase of the disease are intimately related and forecast the development of renal insufficiency many years later. I also will suggest that vasopressin and other hormonal systems exert a modulatory effect on the abnormal cellular phenotype and cyst development caused by PKD mutations. Understanding these interactions is key to the development of effective therapies for ADPKD. Martinez-Maldonado et al[1.Martinez-MALDONADO M. Yium J.J. Eknoyan G. et al.Adult polycystic kidney disease: Studies of the defect in urine concentration.Kidney Int. 1972; 2: 107-113Google Scholar] pointed for the first time to the prevalence of impaired renal concentrating capacity in patients with ADPKD. D'Angelo et al[2.D'ANGELO A. Mioni G. Ossi E. et al.Alterations in renal tubular sodium and water transport in polycystic kidney disease.Clin Nephrol. 1975; 3: 99-105Google Scholar], Preuss et al[3.Preuss H. Geoly K. Johnson M. et al.Tubular function in adult polycystic kidney disease.Nephron. 1979; 24: 198-204Google Scholar], and Gabow et al[4.Gabow P. Kaehny W. Johnson A.M. et al.The clinical utility of renal concentrating capacity in polycystic kidney disease.Kidney Int. 1989; 35: 675-680Google Scholar] confirmed these observations. In fact, the inability to concentrate the urine maximally was part of a proposed algorithm in screening for ADPKD[2.D'ANGELO A. Mioni G. Ossi E. et al.Alterations in renal tubular sodium and water transport in polycystic kidney disease.Clin Nephrol. 1975; 3: 99-105Google Scholar, 3.Preuss H. Geoly K. Johnson M. et al.Tubular function in adult polycystic kidney disease.Nephron. 1979; 24: 198-204Google Scholar, 4.Gabow P. Kaehny W. Johnson A.M. et al.The clinical utility of renal concentrating capacity in polycystic kidney disease.Kidney Int. 1989; 35: 675-680Google Scholar]. More recently, Kaariainen, Koskimies and Norio[5.Kaariainen H. Koskimies O. Norio R. Dominant and recessive polycystic kidney disease in children: Evaluation of clinical features and laboratory data.Pediatr Nephrol. 1988; 2: 296-302Google Scholar] and Seeman et al[6.Seeman T. Dusek J. Vondrak K. et al.Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease.Physiol Res. 2004; 53: 629-634Google Scholar] have shown that approximately 60% of children with ADPKD cannot concentrate the urine maximally after the administration of 1-desamino-[D-Arg8]-vasopressin (dDAVP). Consistent with this concentrating defect, ADPKD patients, like the two patients described here, often exhibit mild degrees of polyuria and like to drink water. Impaired renal concentrating capacity also occurs in other human renal cystic diseases, such as autosomal-recessive PKD (ARPKD), nephronophthisis, and Bardet-Biedl syndrome, and in the animal models of PKD in which it has been studied. The cause of the renal concentrating defect in PKD is not known. A central defect can be ruled out, because plasma vasopressin levels are increased in human ADPKD[6.Seeman T. Dusek J. Vondrak K. et al.Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease.Physiol Res. 2004; 53: 629-634Google Scholar], [7.Danielsen H. Pedersen E.B. Nielsen A.H. et al.Expansion of extracellular volume in early polycystic kidney disease.Acta Med Scand. 1986; 219: 399-405Google Scholar] and in animal models where it has been ascertained (Gattone VH, personal communication). Possible renal causes could be a defect in the principal cells directly linked to the PKD cellular phenotype, early development of tubulointerstitial disease, or disruption of the corticomedullary architecture by the cysts. The up-regulation of aquaporin 2 (AQP2) in polycystic kidneys[8.Gattone V.H. Maser R.L. Tian C. et al.Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease.Dev Genet. 1999; 24: 309-318Google Scholar, 9.Gattone V.H. Wang X. Harris P.C. et al.Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist.Nat Med. 2003; 9: 1323-1326Google Scholar, 10.Torres V.E. Wang X. Qian Q. et al.Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease.Nature Med. 2004; 10: 363-364Google Scholar], in sharp contrast to other forms of nephrogenic diabetes insipidus, suggests increased vasopressin activity and a defect distal to the production of AQP2. The inverse correlation between renal concentrating capacity and extent of cystic disease in children with early ADPKD suggests that the concentrating defect occurs early and is not primarily due to development of tubulointerstitial lesions or disruption of the corticomedullary architecture[6.Seeman T. Dusek J. Vondrak K. et al.Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease.Physiol Res. 2004; 53: 629-634Google Scholar]. Increased plasma vasopressin levels in ADPKD might represent the body's attempt to compensate for the reduced concentrating capacity of the polycystic kidneys and could contribute to the development of renal cysts, hypertension, and renal insufficiency. I will briefly consider the possible effects of vasopressin on the development of hypertension early and on the progression of renal insufficiency late in the disease before discussing in more detail recent advances in the understanding of renal cystogenesis and how this can be influenced by hormonal factors. The observation that plasma vasopressin levels are increased in ADPKD[7.Danielsen H. Pedersen E.B. Nielsen A.H. et al.Expansion of extracellular volume in early polycystic kidney disease.Acta Med Scand. 1986; 219: 399-405Google Scholar], [11.Michalski A. Grzeszczak W. The effect of hypervolemia on electrolyte level and level of volume regulating hormones in patients with autosomal dominant polycystic kidney disease.Pol Arch Med Wewn. 1996; 96: 329-343Google Scholar], particularly in patients with hypertension, raises the issue of whether vasopressin (V) contributes to the development of hypertension in this disease. This could explain the inverse correlation between urine concentrating capacity and average 24-hour blood pressures in children with ADPKD[6.Seeman T. Dusek J. Vondrak K. et al.Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease.Physiol Res. 2004; 53: 629-634Google Scholar] and possibly the direct correlation between urine volume and mean arterial blood pressure detected in the Modification of Diet in Renal Disease (MDRD) study[12.Hebert L.A. Greene T. Levey A. et al.High urine volume and low urine osmolality are risk factors for faster progression of renal disease.Am J Kidney Dis. 2003; 41: 962-971Google Scholar]. V1a and V2 receptors mediate vasopressin's effects on blood pressure. V1a receptor activation might increase blood pressure by a direct effect on vascular smooth muscle and by reducing medullary renal blood flow and pressure natriuresis[13.Cowley JR., A.W. Skelton M.M. Kurth T.M. Effects of long-term vasopressin receptor stimulation on medullary blood flow and arterial pressure.Am J Physiol. 1998; 275: R1420-R1424Google Scholar]. V2 receptor activation increases beta and gamma epithelial sodium channel (ENaC) expression and ENaC function and acts synergistically with aldosterone in the cortical collecting duct (CCD)[14.Nicco C. Wittner M. Distefano A. et al.Chronic exposure to vasopressin upregulates ENaC and sodium transport in the rat renal collecting duct and lung.Hypertension. 2001; 38: 1143-1149Google Scholar]. On the other hand, V2 receptor activation also might exert an antihypertensive effect by inducing nitric oxide (NO) synthesis in collecting ducts and by increasing medullary blood flow[15.Szentivanyi JR., M. Park F. Maeda C.Y. et al.Nitric oxide in the renal medulla protects from vasopressin-induced hypertension.Hypertension. 2000; 35: 740-745Google Scholar]. Impaired NO synthesis, which has been reported in human ADPKD and in animal models of PKD[16.Wang D. Iversen J. Wilcox C.S. et al.Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease.Kidney Int. 2003; 64: 1381-1388Google Scholar], [17.Kocaman O. Oflaz H. Yekeler E. et al.Endothelial dysfunction and increased carotid intima-media thickness in patients with autosomal dominant polycystic kidney disease.Am J Kidney Dis. 2004; 43: 854-860Google Scholar], might be a prerequisite for the hypertensive effect of vasopressin. Vasopressin might play a role in salt-sensitive forms of human and experimental hypertension. Plasma vasopressin levels are higher in “low-renin” and African American hypertensive patients than in normotensive subjects[18.Bakris G. Bursztyn M. Gavras I. et al.Role of vasopressin in essential hypertension: racial differences.J Hypertens. 1997; 15: 545-550Google Scholar]. In untreated hypertensive individuals, plasma vasopressin levels correlate with both systolic and diastolic BP. Vasopressin levels are increased in deoxycorticosterone acetate (DOCA)-salt, Dahl salt-sensitive, Sabra salt-sensitive, and spontaneously hypertensive (SHR) rats. Brattleboro rats with central diabetes insipidus do not develop hypertension when treated with DOCA-salt unless they are supplemented with vasopressin[19.Fernandes S. Bruneval P. Hagege A. et al.Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycorticosterone acetate-salt hypertension.Endocrinology. 2002; 143: 2759-2766Google Scholar]. Dahl salt-sensitive rats have a reduced renal medullary NO synthase activity that makes them more susceptible to the hypertensive effects of vasopressin[20.Yuan B. Cowley JR., A.W. Evidence that reduced renal medullary nitric oxide synthase activity of Dahl s rats enables small elevations of arginine vasopressin to produce sustained hypertension.Hypertension. 2001; 37: 524-528Google Scholar]. Vasopressin regulates the expression of beta and gamma subunits of ENaC in collecting ducts of Sabra rats[21.Nicco C. Bankir L. Bouby N. Effect of salt and water intake on epithelial sodium channel mRNA abundance in the kidney of salt-sensitive Sabra rats.Clin Exp Pharmacol Physiol. 2003; 30: 963-965Google Scholar]. Up-regulation of V1a receptors in preglomerular vessels[22.Vagnes B.O. Hansen F.H. Christiansen R.E. et al.Age-dependent regulation of vasopressin V1a receptors in preglomerular vessels from the spontaneously hypertensive rat.Am J Physiol (Renal Physiol). 2004; 286: F997-F1003Google Scholar] and of V2 receptors[23.Buemi M. Nostro L. Di PASQUALE G. et al.Aquaporin-2 water channels in spontaneously hypertensive rats.Am J Hypertens. 2004; 17: 1170-1178Google Scholar] in collecting ducts is thought to play a role in the development of hypertension in the SHR. The relevance of these observations to ADPKD-associated hypertension, which exhibits many features of salt-sensitive hypertension, deserves consideration. Plasma vasopressin levels are increased in patients with, and animal models of, chronic renal insufficiency[24.Argent N.B. Burrell L.M. Goodship T.H. et al.Osmoregulation of thirst and vasopressin release in severe chronic renal failure.Kidney Int. 1991; 39: 295-300Google Scholar], [25.Bouby N. Bachmann S. Bichet D. et al.Effect of water intake on the progression of chronic renal failure in the 5/6 nephrectomized rat.Am J Physiol. 1990; 258: F973-F979Google Scholar]. Administration of vasopressin or dDAVP to normal rats elevates urea concentration in the thick ascending limb of Henle by increasing intrarenal urea recycling and reduces sodium chloride concentration at the macula densa; these alterations suppress tubuloglomerular feedback and increase glomerular filtration rate (GFR)[26.Bankir L. Ahloulay M. Bouby N. et al.Is the process of urinary urea concentration responsible for a high glomerular filtration rate?.J Am Soc Nephrol. 1993; 4: 1091-1103Google Scholar], [27.Bouby N. Hassler C. Bankir L. Contribution of vasopressin to progression of chronic renal failure: Study in Brattleboro rats.Life Sci. 1999; 65: 991-1004Google Scholar]. Administration of dDAVP to healthy subjects or rats increases urine albumin excretion; this effect is in part mediated by activation of the renin-angiotensin system[28.Bardoux P. Bichet D.G. Martin H. et al.Vasopressin increases urinary albumin excretion in rats and humans: involvement of V2 receptors and the renin-angiotensin system.Nephrol Dial Transplant. 2003; 18: 497-506Google Scholar]. Chronic administration of dDAVP to normal rats induces renal hypertrophy, tubular dilation, and tubulointerstitial disease[29.Naito A. Hasegawa H. Kurasawa T. et al.Histopathological study of kidney abnormalities in an experimental SIADH rat model and its application to the evaluation of the pharmacologic profile of VP-343, a selective vasopressin V2 receptor antagonist.Biol Pharm Bull. 2001; 24: 897-901Google Scholar]. These effects of vasopressin might be particularly relevant to the compensatory hypertrophy and progressive glomerular and interstitial fibrosis that occur in chronic kidney disease. Doubling the daily water ingestion in 5/6 nephrectomized rats lowers plasma vasopressin, urine osmolality, proteinuria, BP, compensatory renal hypertrophy, glomerulosclerosis, and tubulointerstitial fibrosis[25.Bouby N. Bachmann S. Bichet D. et al.Effect of water intake on the progression of chronic renal failure in the 5/6 nephrectomized rat.Am J Physiol. 1990; 258: F973-F979Google Scholar], [30.Sugiura T. Yamauchi A. Kitamura H. et al.High water intake ameliorates tubulointerstitial injury in rats with subtotal nephrectomy: Possible role of TGF-β.Kidney Int. 1999; 55: 1800-1810Google Scholar]. That the attenuation of progression of renal disease in 5/6 nephrectomized Brattleboro rats is reversed by the administration of dDAVP suggests that V2 receptors play a major role in the deleterious influence of vasopressin on disease progression[27.Bouby N. Hassler C. Bankir L. Contribution of vasopressin to progression of chronic renal failure: Study in Brattleboro rats.Life Sci. 1999; 65: 991-1004Google Scholar]. Contrary to these observations, a retrospective analysis of MDRD patients with baseline GFRs of 25 to 55 mL/min/1.73 m2 raised the possibility that a high fluid intake could be detrimental to patients with chronic renal insufficiency, particularly to those with ADPKD[12.Hebert L.A. Greene T. Levey A. et al.High urine volume and low urine osmolality are risk factors for faster progression of renal disease.Am J Kidney Dis. 2003; 41: 962-971Google Scholar]. The patients with the greater urine volumes and the lowest urine osmolalities experienced the fastest declines in GFR. Since these patients tended to have lower serum sodium concentrations and had urines hypotonic to plasma, the authors concluded that excess water intake and not a renal concentrating defect caused the high urine volume. Further studies will be necessary to elucidate the potential beneficial or detrimental effects of high fluid intake in ADPKD patients with renal insufficiency. Since the initial cloning of PKD1 in 1994, the pace of research in ADPKD has accelerated, and an understanding of the PKD phenotype at a cellular level is emerging. I will briefly review these advances and discuss the potential benefits of vasopressin antagonists and related therapies. Polycystin-1 and polycystin-2, the proteins mutated in ADPKD, play an important role in the regulation of [Ca2+]i homeostasis (see[31.Delmas P. Padilla F. Osorio N. et al.Polycystins, calcium signaling, and human diseases.Biochem Biophys Res Commun. 2004; 322: 1374-1383Google Scholar] for a recent review). Polycystin-1 has a large extracellular region, 11 transmembrane domains, and a short cytoplasmic tail. The extracellular region has homology to domains usually involved in protein-protein or protein-carbohydrate interactions and to a family of sperm-expressed sea urchin proteins involved in sperm/egg interactions and the acrosome reaction. The C-terminal tail of polycystin-1 physically interacts with, and regulates the function of, polycystin-2 and also might activate a number of intracellular pathways (G protein, Wnt, and JAK/STAT signaling). Polycystin-2 is smaller than polycystin-1 and is predicted to have cytoplasmic N- and C-termini and 6 transmembrane domains. It acts as a Ca2+-permeable cation channel and its transmembrane region has homology to transient receptor potential channel (TRPC) subunits. The polycystins are found in many subcellular locations, polycystin-1 in focal adhesions, desmosomes, adherens, and tight junctions, and polycystin-2 mostly in the endoplasmic reticulum and possibly, to a much lesser extent, in the plasma membrane (see[31.Delmas P. Padilla F. Osorio N. et al.Polycystins, calcium signaling, and human diseases.Biochem Biophys Res Commun. 2004; 322: 1374-1383Google Scholar] for a recent review). Polycystin-1 in the plasma membrane might interact with polycystin-2 in the adjacent endoplasmic reticulum, similar to the conformational coupling of TRPCs in the plasma membrane and 1,4,5-triphosphate (IP3) receptors in the endoplasmic reticulum. Polycystin-2 also physically interacts with TRPC1[32.Tsiokas L. Arnould T. Shu C. et al.Specific association of the gene product of PKD2 with the TRPC1 channel.Proc Natl Acad Sci USA. 1999; 96: 3934-3939Google Scholar]. Overexpression of polycystin-2 in LLPCK cells amplifies the Ca2+ release from intracellular stores in response to vasopressin stimulation[33.Koulen P. Cai Y. Geng L. et al.Polycystin-2 is an intracellular calcium release channel.Nat Cell Biol. 2002; 4: 191-197Google Scholar]. In vascular smooth muscle cells, a Pkd2 haplo-insufficient state (that is, polycystin-2 content half of normal) is sufficient to significantly reduce capacitative calcium entry and sarcoplasmic reticulum Ca2+ stores[34.Qian Q. Hunter L.W. Li M. et al.Pkd2 haploinsufficiency alters intracellular calcium in vascular smooth muscle cells.Hum Mol Genet. 2003; 12: 1875-1880Google Scholar]. In drosophila, a Pkd2 haplo-insufficient state cannot mediate optimal smooth muscle contractility[35.Gao Z. Joseph E. Ruden D.M. et al.Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility.J Biol Chem. 2004; 279: 14225-14231Google Scholar]. Increases in [Ca2+]i evoked by platelet-activating factor are reduced in B-lymphoblastoid cells isolated from patients with PKD1 or PKD2 mutations[36.Aguiari G. Banzi M. Gessi S. et al.Deficiency of polycystin-2 reduces Ca2+ channel activity and cell proliferation in ADPKD lymphoblastoid cells.FASEB J. 2004; 18: 884-886Google Scholar]. Depletion of polycystin-1 in 293 or Madin-Darby canine kidney (MDCK) cells by an antisense oligodeoxynucleotide to levels approximately one-half those found in control cells induces cell proliferation and premature G1/S-phase transition[37.Kim B.Y. Ahn J.B. Lee H.W. et al.Synthesis and biological activity of novel substituted pyridines and purines containing 2,4-thiazolidinedione.Eur J Med Chem. 2004; 39: 433-447Google Scholar]. Insertion of a neomycin cassette into intron 1 of Pkd1 reduced Pkd1 transcript levels to 20% of control because of aberrant splicing and caused polycystic kidneys[38.Lantinga-VAN LEEUWEN I.S. Dauwerse J.G. Baelde H.J. et al.Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease.Hum Mol Genet. 2004; 13: 3069-3077Google Scholar]. This animal model demonstrates that cystogenesis might result from a reduction in polycystin-1 levels and does not always require complete lack or inactivation of this protein. Recent studies have focused on the localization of the polycystin complex in primary cilia and on its well-documented role in mediating calcium fluxes in response to mechanical stimulation[39.Nauli S.M. Alenghat F.J. Luo Y. et al.Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells.Nat Genet. 2003; 33: 129-137Google Scholar], [40.Mcgrath J. Somlo S. Makova S. et al.Two populations of node monocilia initiate left-right asymmetry in the mouse.Cell. 2003; 114: 61-73Google Scholar]. Every epithelial cell in the kidney, with the exception of the intercalated cells, is decorated by a single primary cilium. A primary cilium consists of a membrane continuous with the cell membrane and a central axoneme comprising nine microtubule doublets[41.Poole C.A. Zhang Z.J. Ross J.M. The differential distribution of acetylated and detyrosinated alpha-tubulin in the microtubular cytoskeleton and primary cilia of hyaline cartilage chondrocytes.J Anat. 2001; 199: 393-405Google Scholar, 42.Zhang Q. Taulman P.D. Yoder B.K. Cystic kidney diseases: All roads lead to the cilium.Physiology (Bethesda, MD). 2004; 19: 225-230Google Scholar, 43.Snell W.J. Pan J. Wang Q. Cilia and flagella revealed: from flagellar assembly in Chlamydomonas to human obesity disorders.Cell. 2004; 117: 693-697Google Scholar]. The cilium originates from, and is rooted in, a basal body or mother centriole in the centrosome. The centrosome is found in proximity to the Golgi apparatus and constitutes the microtubule organizing center of the cell. It consists of a mother and a daughter centriole and pericentriolar material surrounding the mother centriole. In non-dividing cells, the distal end of the mother centriole gives rise to the primary cilium. The primary cilium in differentiated renal epithelial cells has mechanosensory and chemosensory functions[44.Praetorius H.A. Spring K.R. Bending the MDCK cell primary cilium increases intracellular calcium.J Membr Biol. 2001; 184: 71-79Google Scholar], [45.Praetorius H.A. Praetorius J. Nielsen S. et al.Beta1-integrins in the primary cilium of MDCK cells potentiate fibronectin-induced Ca2+ signaling.Am J Physiol (Renal Physiol). 2004; 287: F969-F978Google Scholar]. During the S-phase, the primary cilium is reabsorbed and the centrioles duplicate into new mother and daughter centrioles. During mitosis the new centrosomes are at the poles of the mitotic spindle and primary cilia are absent. Growth and reabsorption of the primary cilium during the cell cycle require continuous transport of proteins to and from the tip of the cilia. This transport occurs in aggregates called rafts and is driven by two motor proteins, kinesin II (anterograde) and cytoplasmic dynein (retrograde transport). Disruption of primary cilia in principal cells by a kidney-specific knockout of a kinesin II subunit (KIF3A) results in rapid development of polycystic kidneys[46.Lin F. Hiesberger T. Cordes K. et al.Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease.Proc Natl Acad Sci USA. 2003; 100: 5286-5291Google Scholar]. Inactivation of hepatocyte nuclear factor-1β (HNF1β), a transcription factor in the ciliary and basal body proteome, down-regulates the expression of five PKD proteins (uromodulin, fibrocystin, polycystin-2, nephrocystin-1, and polaris) and results in polycystic kidneys[47.Gresh L. Fischer E. Reimann A. et al.A transcriptional network in polycystic kidney disease.EMBO J. 2004; 23: 1657-1668Google Scholar], [48.Hiesberger T. Bai Y. Shao X. et al.Mutation of hepatocyte nuclear factor-1b inhibits Pkhd1 gene expression and produces renal cysts in mice.J Clin Invest. 2004; 113: 814-825Google Scholar]. The association of proteins mutated in PKDs and the centrosome is not limited to the interphase. It also occurs during mitosis, as it has been reported for inversin, BBS4, and polycystin-2[49.Morgan D. Eley L. Sayer J. et al.Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle.Hum Mol Genet. 2002; 11: 3345-3350Google Scholar, 50.Kim J.C. Badano J.L. Sibold S. et al.The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.Nat Genet. 2004; 36: 462-470Google Scholar, 51.Rundle D.R. Gorbsky G. Tsiokas L. PKD2 interacts and co-localizes with mDial1 to mitotic spindles of dividing cells.J Biol Chem. 2004; 279: 29728-29739Google Scholar]. Loss of polycystin-2 localization to the mitotic spindles by knockdown of the interacting cytoskele