Pediatr Nephrol (2005) 20:558–566 DOI 10.1007/s00467-004-1665-z

REVIEW

John J. Bissler · Bradley P. Dixon A mechanistic approach to inherited polycystic kidney disease

Received: 24 June 2004 / Revised: 5 August 2004 / Accepted: 17 August 2004 / Published online: 18 February 2005 IPNA 2005

Abstract There are approximately six and a half million them as specific disease states (Table 1). The elucidation people, of the estimated world population of six billion, of a unifying mechanism leading to cystogenesis has been with inherited polycystic kidney disease. Polycystic kid- hampered by the phenotypic variability. The unexpected ney diseases have a broad spectrum of associated findings association of the primary with several inherited that distinguish and define them as specific disease states. polycystic kidney diseases has indicated a role for this The dysregulation of renal tubular epithelial cell biology, previously understudied organelle and has emphasized the including cell polarity, cell signaling, proliferation and importance of sensor-driven feedback loops in tubule apoptosis, basement membrane and matrix abnormalities, morphogenesis. and fluid transport, has been postulated to contribute to cystogenesis. Evidence is currently accumulating that supports an association of the primary cilium and basal Disease burden body, as well as the focal adhesion assembly, with poly- cystic kidney diseases. Renal cystogenesis may be the There are approximately six and a half million people, of result of a disruption of a critical feedback loop that the estimated six billion world population, with one of the regulates tissue morphology based on the epithelial cell inherited polycystic kidney diseases. The incidence and environment. prevalence of inherited polycystic kidney diseases from individual studies can be used to extrapolate an estimated Keywords Polycystic kidney disease · Nephronophthi- worldwide number of affected patients as shown in sis · Medullary cystic kidney · Tuberous sclerosis Figs. 1 and 2. Although some of these inherited cystic complex · Bardet-Biedl syndrome · Cilia diseases are rarely encountered by the practitioner, the number of affected people justifies the investigations into their pathogenesis. Introduction Genetics Discovery is seeing what everyone else has seen and thinking what no one else has thought. Albert Szent-Gy- Autosomal dominant disease orgi von Nagyrapolt (1893–1986) Autosomal dominant disease can be phenotypically ex- Inherited polycystic kidney diseases have a broad spec- pressed by one of four mechanisms. If a mutation in the trum of associated findings that distinguish and define disables the production of a functional , and the remaining allele cannot produce enough protein, dis- J. J. Bissler · B. P. Dixon ease is said to develop through “haploinsufficiency.” If Division of Nephrology and Hypertension, the mutation results in a new function of the protein, then Cincinnati Children’s Hospital Medical Center, the autosomal dominant disease is said to be due to a Cincinnati, OH 45229-3039, USA “gain-of-function” mutation. If the mutant protein blocks J. J. Bissler ()) the activity of the normal protein produced by the normal Children’s Hospital Research Foundation, allele, then the mutation is termed “dominant negative.” ML 7022, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA Lastly, cells harboring a germline mutation can lose the e-mail: [email protected] function of the normal allele by somatic mutation. This Tel.: +1-513-6364531 process, referred to as the “second hit,” results in a cell Fax: +1-513-6367407 559 Table 1 Inherited renal cystic diseases. The age at onset, renal imaging, and extrarenal manifestations are for the classical forms of disease although there can be wide variation (AD autosomal dominant, AR autosomal recessive) Inherited cystic disease Inheritance Age at onset Renal imaging Extrarenal manifestations Autosomal dominant AD Adulthood Isolated renal cysts in early childhood Hepatic and pancreatic cysts polycystic kidney disease Multiple large cysts later in adulthood Cerebral vessel aneurysms Mitral valve prolapse Tuberous sclerosis complex AD Childhood Angiomyolipoma, simple or multiple Adenoma sebaceum, ungual cysts fibromas Polycystic in contiguous gene Cardiac rhabdomyomas syndrome (TSC2and PKD1) Hypopigmented macules and shagreen patch Medullary cystic disease AD Early Normal or reduced size, echogenic Hyperuricemia and gout adulthood Loss of corticomedullary differentiation Cysts at the corticomedullary border Autosomal recessive AR Neonatal Large echogenic kidneys Biliary dysgenesis and hepatic polycystic kidney disease childhood Poor corticomedullary differentiation fibrosis Nephronophthisis AR Infantile Normal size, increased echogenicity childhood Loss of corticomedullary (Senior-Loken syndrome) adolescent differentiation, cysts at the Oculomotor apraxia corticomedullary border Cone-shaped epiphyses Exaggerated anemia

Bardet-Biedl syndrome Complex AR Childhood Fetal lobulation Obesity, polydactyly, mental Calyceal cysts, diverticula and retardation clubbing Retinal dystrophy and Cystic dysplasia hypogenitalism

Fig. 1 Polycystic disease inherited as autosomal dominant traits. ium (ADPKD autosomal dominant polycystic kidney disease, TSC The number of affected is based upon an estimated world popula- tuberous sclerosis complex, MCKD medullary cystic kidney dis- tion of six billion. The locations and protein products are ease) indicated. All in blue are associated with the primary cil- that cannot produce a functional protein. This mechanism medullary cystic kidney disease/nephronophthisis com- was first postulated by Knudson [1] to describe events in plex has been coined. Although their histology is identi- retinoblastoma. cal, their inheritance is distinct. Medullary cystic disease is inherited as an autosomal dominant disease, while nephronophthisis is an autosomal recessive disease. Autosomal dominant renal cystic diseases Medullary cystic disease is also associated with hyperu- ricemia and two loci have been identified. Mutations have Medullary cystic kidney disease been found in the MCKD2 gene that result in an absent or altered protein called uromodulin (Fig. 1). Similar muta- Medullary cystic disease and nephronophthisis have so tions were also identified in familial juvenile hyperuri- many clinical and pathological similarities that the term cemic nephropathy, indicating that both medullary cystic 560

Fig. 2 Polycystic disease inherited as autosomal recessive traits. (ARPKD autosomal recessive polycystic kidney disease, NPH The number of affected is based on a world population of six nephronophthisis, BBS Bardet-Biedel syndrome) billion. All proteins in blue are associated with the primary cilium kidney disease with hyperuricemia and familial juvenile giomyolipomata and cysts. Although approximately 70% hyperuricemic nephropathy are allelic forms [2]. The of patients exhibit renal angiomyolipomata, only 35% exact function of uromodulin, also known as Tamm- have renal cysts [11] and roughly half of these have Horsfall protein, is unknown but it has been shown to clinically significant, multiple cysts. The cysts may be have immunomodulatory activity; this activity is intrigu- large, but are usually neither numerous nor problematic. ing given the interstitial infiltrative component of this An exception is the polycystic kidney disease phenotype disease [3, 4]. of TSC. This phenotype is due to disruption of the TSC2 gene and the very closely adjacent PKD1 gene, resulting in a patient with both TSC and ADPKD [12, 13]. This Autosomal dominant polycystic kidney disease phenotype is estimated to occur in approximately 2% of TSC patients, and the cystic disease and resultant hyper- Autosomal dominant polycystic kidney disease (ADPKD) tension manifest very early in life. affects 1 in 1,000 people, regardless of race or ethnicity. There are two known genes associated with ADPKD (Fig. 1). Mutations in one gene, known as PKD1, account Autosomal recessive diseases for 85%–90% of cases. Mutations in the other gene, known as PKD2, result in a similar phenotype, but the When both alleles at a non-sex-linked locus are mutant, manifestations are less severe and end-stage renal disease no functional protein is produced. If this leads to a dis- tends to be reached later [5]. Very rare families fail to tinguishable phenotype, the inheritance is said to be au- have linkage to either of these loci, suggesting a third tosomal recessive. The genetic loci for both autosomal locus. One such rare family was discovered to have si- recessive polycystic kidney disease (ARPKD) and neph- multaneous linkage to both PKD1 and PKD2 genes rather ronophthisis are on autosomes, and some forms of Bardet- than linkage to a third locus [6]. Biedl syndrome may have a complex autosomal recessive All affected members of a kindred share the same inheritance. germline mutation, but the intrafamilial phenotypic ex- pressivity varies widely. This indicates that disease- modifying processes are operating. For ADPKD, this Autosomal recessive polycystic kidney disease could be ascribed to disease-modifying genes similar to those so elegantly demonstrated in the animal models of ARPKD is a common pediatric renal cystic disease, with renal cystic disease [7]. While it is possible that all four an estimated incidence of 1 in 20,000 live births [14]. The mechanisms that lead to the expression of autosomal phenotypic expression of disease is variable and the dis- dominant disease may contribute to ADPKD, the two ease manifestations correlate with the age of presentation most likely include haploinsufficiency [8] and the second- (Fig. 2). Mutations in the recently cloned PKHD1 (poly- hit mechanism [9, 10]. cystic kidney and hepatic disease 1) gene [15, 16] account for the typical forms of ARPKD [17] (Fig. 2). Although the diagnostic approach using direct sequencing is ham- Tuberous sclerosis complex pered by a suboptimal detection of mutation, a reliable, haplotype-based diagnostic test is available for at-risk The TSC1 and TSC2 genes are associated with the renal pregnancies [14]. PKHD1 is a large gene and exhibits disease seen in tuberous sclerosis complex (TSC) (Fig. 1). considerable alternative splicing that is predicted to result Renal lesions in TSC are common and include an- in numerous membrane-bound and secreted proteins [16]. 561 Nephronophthisis Cell biology

Nephronophthisis is inherited in an autosomal recessive The dysregulation of renal tubular epithelial cell biology manner; however, the age of progression to end-stage that leads to cyst formation has been divided into four renal disease is variable, resulting in the classification as basic categories: (1) cell polarity, (2) proliferation and infantile, juvenile, and adolescent forms. Mutations of the apoptosis, (3) basement membrane and matrix abnor- NPH1 gene are responsible for most juvenile forms of malities, and (4) fluid transport. nephronophthisis (Fig. 2). A large homozygous deletion within the NPH1 gene has been demonstrated in ap- proximately 80% of individuals with disease associated Cell polarity with this gene [18]. The function of nephrocystin, the NPH1 gene product, is not clear. The protein contains a A well-studied derangement found in epithelial cells lin- src-homology 3 (SH3) domain, supporting the hypothesis ing cysts is the disruption of cell polarity. Cell polariza- that it is part of the focal adhesion-signaling complex. The tion normally occurs during nephron maturation. This infantile form of nephronophthisis has been linked to the process fails to occur in the cystic . Intermo- inv gene at 9q22–31 that produces inversin, a locus pre- lecular interactions between endogenous cellular poly- viously identified in a mouse model of polycystic kidney cystin-1 and the adhesion protein E-cadherin appear to be disease. The adolescent form of nephronophthisis has critical for the institution and perpetuation of epithelial been linked to 3q21–22 at the NPH3 gene that produces cell polarity [23]. The epithelial cells from cysts exhibit the protein called nephrocystin-3. A fourth gene locus for altered cytoarchitecture and protein trafficking along with nephronophthisis that encodes the nephroretinin protein apical mis-localization of the epidermal growth factor has been mapped to 1p36. Nephroretinin is a receptor and abnormalities of expression of multiple unique, evolutionarily conserved protein that is devoid of proteins, including cathepsin B, matrix metalloproteinase conserved domains, signal sequences, or predicted trans- 2, and E-cadherin [24]. membrane regions. Glutamate- and proline-rich regions are found at the N-termini of both nephrocystin and nephroretinin. These two proteins have a similar wide- Proliferation and apoptosis spread tissue distribution and appear to interact, sug- gesting they may participate in the same signaling path- Cell cycle abnormalities are also detected in cystic cells. way [18]. Polycystin-1 activates the JAK-STAT pathway and up- waf1 A variant of nephronophthisis has been described with regulates p21 , thereby inducing G0/G1 arrest. This the additional manifestation of retinitis pigmentosa. This process requires the correct expression of polycystin-2. combination of renal and ocular disease has been referred Mutations that change the expression of either polycystin- to by several names including renal-retinal and Senior- 1 or 2 cause abnormalities in the function of the JAK- Loken syndromes. Linkage to various forms of this syn- STAT pathway, leading to dysregulated growth [25]. drome co-localize with nephronophthisis loci (NPH1, Using Madin-Darby canine kidney (MDCK) cells grown NPH3, and NPH4), and deletions involving both the in a three-dimensional collagen gel model, Lin et al. [26] NPH1 and NPH4 loci have been identified in separate also implicated apoptosis as a key step in the formation of kindred. The retinal addition to the disease phenotype has cysts. It is highly likely that abnormalities in both cell been postulated to be secondary to modifier genes [19]. proliferation and apoptosis contribute to cystogenesis.

Bardet-Biedl syndrome Basement membrane and matrix abnormalities

The Bardet-Biedl syndrome has been linked to eight Polycystic kidneys exhibit thickened basement mem- genes (Fig. 2). Initially thought to be a simple recessive branes with alterations in matrix composition and an in- disorder, some forms of Bardet-Biedl syndrome require creased number of integrin receptors on cystic epithelium recessive mutations in one of the eight loci plus an ad- [27]. As a result, the cystic epithelial cells adhere more to ditional mutation in a second locus, also called ‘triallelic matrixes comprised of type I or IV collagen than to inheritance’ [20] or ‘recessive inheritance with a modifier normal epithelial cells [28]. of penetrance’ [21]. A rough estimate of disease preva- lence is 1 in 135,000, but it is 10 times more frequent in the Bedouin population [22]. Fluid transport Bardet-Biedl syndrome is characterized by mental re- tardation, pigmentary retinopathy, polydactyly, obesity, Misdirected fluid transport has been proposed to contribute renal abnormalities, and hypogenitalism. In the neonatal to cystogenesis. Renal sodium, and hence fluid, transport is period, it can be misdiagnosed as the Kaufman-McKusick facilitated by positioning the sodium transporter (Na+/K+- syndrome, but the diagnosis becomes clear with the later ATPase) at the basolateral aspect of the renal tubular cell. development of obesity and retinal dystrophy. Positioning of these transporters is developmentally regu- 562

Fig. 3 Tubular portion involved in cystogenesis. The diagram at be involved in cystogenesis during the early developmental period. the top depicts a linearized nephron and the black lines below The gradient for the line for autosomal dominant polycystic disease illustrate the portion of the nephron that appears to be involved in indicates that cysts develop predominantly in the collecting duct cystogenesis. The dashed line indicates that the proximal tubule can lated. In the adult, the a1b1 isoform is expressed at the communicate with the nephron, although there are cur- basolateral surface and functions to facilitate reabsorption. rently limited data on this topic. ARPKD, nephronoph- This is quite different in the fetus. The fetus expresses the thisis/medullary cystic kidney disease complex [36], and a1b2 isoform on the apical, or luminal surface and in this Bardet-Biedl syndrome [37] all appear to involve the position would appear to be involved in fluid secretion. collecting duct. Recent advances have produced evidence Some investigators have reported that the epithelial cells that the primary cilium, cell-matrix focal adhesion, and from cysts likewise express the a1b2 isoform in an apical cell-cell adherens junction all play a role in cystogenesis. distribution [29]. The Na+,K+,2Cl- symporter is also misplaced to the basal surface [30]. The net result of this transporter positioning could be to secrete fluid into the Cilium cyst, although the magnitude of this secretion is unclear. Aquaporin abnormalities also have been identified. Both Primary cilia are organelles that originate from the basal aquaporin-1 and aquaporin-2 water channels are found in body and are associated with the . The primary cystic epithelial cells in ADPKD; aquaporin-2 water cilium, which contains a central composed of channels are identified in the epithelial cells from cysts nine doublets of microtubules that project from the cell, is associated with ARPKD. These channels could further covered by a membrane that is contiguous with the facilitate fluid secretion into the cystic lumen. Proposed plasma membrane [38]. The proteins kinesin and mechanisms of secretion for ADPKD also include an in- are responsible for the intraflagellar traffic. One or two crease in intracellular cAMP and CFTR expression, while primary cilia are found in all kidney epithelial cells except a downregulation of the amiloride-sensitive Na transport is the intercalated cells. These cilia protrude into the lumen associated with ARPKD [31]. of the tubule and are in contact with the urine (Fig. 4). The cilia are believed not to be motile or propel the urine. They were previously described as vestigial organelles, New insights into pathogenesis but recent findings suggest otherwise. Evidence is currently accumulating supporting a strong Cysts and tubules association between the primary cilium, , and polycystic kidney disease. Deflection of the renal epi- The development of cysts from renal tubules has long been thelial primary cilium is associated with a significant postulated. Microdissection studies and fluid analyses calcium flux mediated by polycystin-1 and -2 [39]. Use of have identified the origin of cysts along the nephron the MDCK cell model has clearly identified an associa- (Fig. 3). In both ADPKD and TSC, cysts have been re- tion between cilium deflection and calcium currents [40, ported to originate anywhere along the nephron. In 41, 42]. This association would imply that the epithelial ADPKD, histographic [32] and immunohistochemical [33, primary cilium may function as a flow sensor, and in this 34] evidence suggests that cysts originate predominantly role could be extremely important in governing mor- from the collecting duct. Studies by Potter [35] suggest phology considering the exponential relationship between that the cysts in patients with tuberous sclerosis may still flow and radius of the conduit. A sensor function for cilia 563 Fig. 4 Diagram depicting the primary cilium, cell-cell and cell matrix adherens junctions. Signaling by the adherens junction can be mediated di- rectly or through b-catenin. The possible role of these and other proteins in cystogenesis is in- cluded. The flow in the tubule could be detected by cilial de- flection. Such an organization would be exquisitely sensitive to the flow and tubular diameter relationship

has long been recognized in sensory perception as is cilium and seems to concentrate in the region of the basal found, for example, in the rods and cones of the retina. body [44, 45]. Inversin, the protein product of the inv gene The outer segments of these photoreceptors are derived associated with infantile nephronophthisis, has also been from cilia. localized to the primary cilium [46]. Given the role of cilia Polycystin-1 and -2 have been localized to the renal in vision, intriguing questions are raised about the renal- primary cilium [43] and mediate mechanosensation [39]. retinal syndromes. Likewise, polaris and cystin, proteins This association with the cilium is even stronger for the associated with a polycystic kidney disease phenotype in autosomal recessive diseases. There is evidence that all mice, also localize to the primary cilium [43]. Bardet- proteins associated with the recessive diseases may be Biedl syndrome also appears to be caused by a defect of involved with the primary cilium (Fig. 2). , the the basal body of ciliated cells [47]. The TTC8 gene protein associated with ARPKD, localizes to the primary (Fig. 2) encodes BBS8, a protein with strong homology to 564 a prokaryotic domain, pilF, that is intricately involved in pilus formation and twitching mobility [47]. A family with a homozygous null TTC8 mutation also exhibited ran- domization of left-right body axis symmetry and a defect of the nodal cilium reminiscent of the murine polycystic kidney disease models inv [46, 48] and orpk [49]. The BBS8 protein localizes to and basal bodies and co-localizes with gamma-, BBS4, and PCM1, a protein known to interact with BBS4 [47]. Because the phenotype of Bardet-Biedl syndrome is so similar irre- spective of the locus involved, Ansley et al. [47] examined all available Caenorhabditis elegans BBS homologues and found that they all are expressed exclusively in ciliated neurons. All the genes for these homologues contain regulatory elements for a transcription factor, RFX, which is known to modulate the expression of genes associated with ciliogenesis and .

Fig. 5 Block diagram representing morphogenesis feedback con- Cell-matrix focal adhesion trol loop. Signals, in the form of and/or post- translational modifications such as phosphorylations, feed the ef- Other critical information about tubular architecture is fecter limb and regulate cell proliferation and apoptosis. The in- tended output is the very ordered tubular array. The resultant tissue also gathered by the cell from the focal adhesion assem- architecture may be probed by sensors such as cilia and adhesion bly that includes polycystins. The association of poly- junctions shown in the red box, and deviations that are sensed can cystin-1 with the focal adhesion complex is derived from be corrected by changes in the output by the supervisor, or nucleus. co-immunoprecipitation, sedimentation, and localization Loss of the sensor function disrupts the feedback control loop studies. These demonstrate that polycystin-1 interacts permitting unregulated effecter output and abnormal morphogene- sis, in this case, cystogenesis with a1b2 integrin, vinculin, paxillin, c-src, p130cas, talin, and focal adhesion kinase [28, 50]. Although focal ad- hesion kinases were initially associated with cell migra- expression and/or post-translational modifications such as tion, they also can transduce and affect the strain of cells phosphorylation lead to cell proliferation and apoptosis, on their basement membrane [51]. Signaling from the which choreograph the development of the tubule in an cell-matrix interface would seem to be a logical compo- ordered array. For this complex event to occur, the cells nent in establishing cell polarity. must have some sort of feedback to assure the proper architecture is achieved. The cells may survey tubule development through signals from cilia and adhesion Cell-cell adherens junction junctions. Sensed deviations are corrected. Disruption of this feedback control loop permits dysregulated devel- The cell collects architecture input data from its available opment and abnormal morphogenesis, in this case, cys- three-dimensional sources. In addition to luminal and togenesis. basement membrane inputs, additional information about Such a model is useful not only for understanding tissue architecture of renal tubular epithelial cell is gath- possibilities for pathogenesis, but also for understanding ered from neighboring cells. Polycystin-1 has been lo- potential therapeutic approaches to polycystic disease. calized to apical-lateral cell boundaries in vitro, and co- While currently there are no cures, current research offers immunoprecipitation, sedimentation, and localization great hope. Recent work focusing on growth factor re- studies demonstrate that polycystin-1 interacts with E- ceptor polarity has offered insights into autosomal re- cadherin, b-catenin, and g-catenin [23, 50]. Functional cessive disease [53, 54]. Studies of calcium and cAMP studies reveal that a primary function of polycystin-1 is to signaling provide very encouraging evidence that not only mediate cell-cell adhesion in renal epithelial cells. This can progression of the cystic disease phenotype be mod- adhesion may be mediated through homophilic or het- ified in an animal model, but it can also be reversed [33, erophilic interactions of its PKD domains. Loss of such 55]. cell-cell adhesion during tubular morphogenesis may trigger cyst formation in ADPKD [52]. Acknowledgements The bibliography is restrained by space limi- tations, and the authors apologize to the scientists whose work has not been cited. The authors would like to thank Drs. Vincent Torres, Clark D. West, and Lisa Guay-Woodford for their careful Sensor malfunction review of the manuscript and constructive comments. 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