Polycystic Kidney Disease - Loyola Medicine · n engl j med 350;2 january 8, 2004 The new england...

n engl j med

350;2

www.nejm.org january

8, 2004

The

new england journal

of

medicine

151

review article

mechanisms of disease

Polycystic Kidney Disease

Patricia D. Wilson, Ph.D.

From the Department of Medicine, Divi-sion of Nephrology, Mount Sinai School ofMedicine, New York. Address reprint re-quests to Dr. Wilson at the Department ofMedicine, Division of Nephrology, MountSinai School of Medicine, 1425 MadisonAve., East Bldg., Rm. 11-23, New York, NY10029, or at [email protected].

N Engl J Med 2004;350:151-64.

Copyright © 2004 Massachusetts Medical Society.

olycystic kidney diseases are a leading cause of end-stage re-

nal failure and a common indication for dialysis or renal transplantation. Re-cent advances have led to insights into mechanisms underlying the cause and

prognosis of these diseases and suggest new directions for treatment.Polycystic kidney disease may arise sporadically as a developmental abnormality or

may be acquired in adult life, but most forms are hereditary. Among the acquired forms,simple cysts can develop in kidneys as a consequence of aging; dialysis, drugs, and hor-mones can cause multicystic disease

1,2

; and renal cysts are often secondary manifes-tations of genetic proliferative syndromes.

1

The inherited polycystic kidney diseases,which are due to germ-line mutations in single genes, inherited as mendelian traits, in-clude autosomal dominant and autosomal recessive polycystic kidney disease, neph-ronophthisis, and medullary cystic diseases. The age at onset, the severity of symptoms,and the rates of progression to end-stage renal failure or death vary widely in this groupof diseases.

Autosomal dominant polycystic kidney disease, the most common form of polycystickidney disease, occurs in 1 in 800 live births. It affects 500,000 persons in the UnitedStates and 4 million to 6 million worldwide and is the reason for hemodialysis in 7 to 10percent of patients. There are two types: type I is caused by mutations in the

PKD1

geneand accounts for 85 to 90 percent of cases,

3

and type II is caused by mutations in the

PKD2

gene and accounts for 10 to 15 percent of cases

4

(Table 1). The protein productsof these two genes, polycystin-1 (Fig. 1A) and polycystin-2 (Fig. 1B), occur on renal tu-bular epithelia. Polycystin-1 is a membrane receptor capable of binding and interactingwith many proteins, carbohydrates, and lipids and eliciting intracellular responsesthrough phosphorylation pathways, whereas polycystin-2 is thought to act as a calci-um-permeable channel. The two types of autosomal dominant polycystic kidney dis-ease have similar pathological and physiological features, but type II disease has a lateronset of symptoms and a slower rate of progression to renal failure; thus, patients havea longer life expectancy (69.1 years) than those with type I disease (53.0 years).

6

Somepatients with typical features of autosomal dominant polycystic kidney disease have nomutations in

PKD1

or

PKD2,

suggesting that there may be a rare third form of the dis-ease,

7

although the proposed gene —

PKD3

— has not been identified. Patients withmutations in both the

PKD1

and

PKD2

genes (transheterozygotes) have a more severeclinical course than those with mutations in only one of the genes.

8

Tremendous cystic enlargement of both kidneys is characteristic of autosomal dom-inant polycystic kidney disease. Patients often present with hypertension, hematuria,polyuria, and flank pain and are prone to recurrent urinary tract infections and renalstones. In addition to the presence of hundreds to thousands of renal cysts, up to 10 to

p

autosomal dominant polycystic kidney disease

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20 cm in diameter, clinically significant cysts arealso common in the liver (especially in women),pancreas, and intestine. Patients have an in-creased risk of aortic aneurysms and heart-valvedefects,

9

and some kindreds have five times therisk in the general population of sudden death fromruptured intracerebral aneurysms.

10

Autosomal recessive polycystic kidney disease ismuch rarer than the autosomal dominant form,with an incidence of 1 in 20,000 live births, and oftencauses fetal or neonatal death owing to tremendous

autosomal recessive

polycystic kidney disease

* AD denotes autosomal dominant, and AR autosomal recessive.

† Data are from Otto et al.

5

Table 1. Characteristics of Inherited Polycystic Kidney Diseases.

DiseaseMechanism ofInheritance*

AberrantGene

ChromosomalLocation

Length ofTranscript

ProteinEncoded

MolecularMass

kb kD

Polycystic kidney disease

Autosomal dominant ADAD

PKD1PKD2

16p13.34q21

14.55.6

Polycystin-1Polycystin-2

462110

Autosomal recessive AR

PKHD1

6p21–23 16.2 Fibrocystin 447

Nephronophthisis

Juvenile AR

NPH1

2q12–13 4.5 Nephrocystin 83

Infantile† AR

NPH2

9q22–31 5 Inversin 98

Adolescent AR

NPH3

3q21–22 ? ? ?

Medullary cystic kidney disease ADAD

MCKD1MCKD2

1q2116p12

??

??

??

Figure 1 (facing page). Structure of Polycystic Kidney Disease Proteins.

The gene for autosomal dominant polycystic kidney disease (

PKD1

) encodes a 462-kD protein — polycystin-1 (Panel A) — composed of a long extracellular N-terminal portion, 11 transmembrane domains, and a short intracellular C-termi-nal portion. Multiple domains are seen in the extracellular portion, including two cysteine-flanked (C) leucine-rich re-peats (LRR), capable of binding collagen, fibronectin, and laminin; a cell-wall integrity and stress-response component (WSC) homology domain suggesting that the protein may be able to bind carbohydrates; the first of 16 IgG-like repeats, which binds receptor protein tyrosine phosphatases; a low-density lipoprotein A (LDL-A)–related domain; a C-type lectin domain that binds carbohydrate in a calcium-dependent fashion; 15 more IgG-like repeats with surface

b

-pleated folds and the capacity to bind protein ligand; and a receptor for egg jelly (REJ) homology domain and a latrophilin (CL-1–like GPS) domain suggestive of a protein-cleavage site. The potential of the protein to interact with lipids is also suggested by the presence of a lipoxygenase (LH

2

) domain on the intracellular side of the first transmembrane. The 200-amino-acid intracellular C-terminal tail contains several protein-interaction and phosphorylation-signaling sites, including a coiled-coil domain, a heterotrimeric G-protein–activation site (GPAS), and two proline-rich sites — src homology 3 (SH

3

) and putative WW — as well as specific tyrosine sites for phosphorylation by c-src (at amino acid Y4237 in the YEMV consensus sequence) and focal adhesion kinase (FAK) (at amino acid Y4127) and serine phosphorylation sites by protein kinase A (PKA) (at amino acid S4252 in the RSSR consensus sequence) and protein kinase X (PRKX) (at amino acid S4161). The gene for autosomal dominant polycystic kidney disease (

PKD2

) encodes polycystin-2 (Panel B), a 110-kD protein that is part of the transient receptor potential family of calcium and sodium channels. It is composed of six transmembrane domains with a pore homology region in the extracellular loop between transmembrane domains 5 and 6 and the intracellular N- and C-terminal domains as well as a putative actin-binding (HAX) domain. The C-terminal con-tains a coiled-coil domain, putative phosphorylation sites, and an EF hand domain. The gene for juvenile nephronoph-thisis (

NPH1

) encodes nephrocystin (Panel C), an 83-kD intracellular protein with an N-terminal coiled-coil domain, two acidic regions, and an SH

3

domain that binds to the focal adhesion proteins p130cas and tensin. The gene for autoso-mal recessive polycystic kidney disease (

PKHD1

) encodes fibrocystin (Panel D), a 447-kD protein with a long extracellu-lar N-terminal portion, one transmembrane domain (TMEM), and a short intracellular C-terminal portion. The extracel-lular portion contains immunoglobulin-like domains (TIG), suggesting that the protein can bind other proteins, and the intracellular portion contains putative serine phosphorylation sites by protein kinase A (PKA) or protein kinase C (PKC).



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A Polycystin-1

D Fibrocystin

B Polycystin-2C C

N

C

CPKA or PKC

DKFZ

TMEM

TIG

N

WSC

LRR

N

PKD-1 IgG-like

REJ

LDL-A

C-type lectin

LH2

WW

FAKYEMY

RSSR

RSSR

PKA

SRC

SH3

GPAS

SH3

EF

Coiledcoil

HAX

Coiledcoil

PRKX

CL-1–like GPS

PKD-1 IgG-like

C

N

SH3Acidic Acidic

C Nephrocystin



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bilateral enlargement of the kidneys, impaired lungformation, and pulmonary hypoplasia. Renal fail-ure and hepatic fibrosis develop in most babies whosurvive the perinatal period. The disease is character-ized by the expansion and elongation of collectingtubules into multiple small cysts and by biliary dys-genesis. Mutations in the

PKHD1

gene cause auto-somal recessive polycystic kidney disease

11,12

(Ta-ble 1 and Fig. 1D). The identification of a mild formof the disease

13

suggests that additional genes areinvolved.

Familial nephronophthisis is inherited as a reces-sive trait. Three distinct types — juvenile, adoles-cent, and infantile — are caused by mutations inthe

NPH1

(Fig. 1C),

NPH2,

and

NPH3

genes, respec-tively.

14-16

In nephronophthisis, both kidneys areshrunken and the renal cysts are restricted to themedulla at its border with the cortex. The typical clin-ical manifestations are salt wasting, growth retar-dation, anemia, polyuria, and progressive renal in-sufficiency.

The two distinct types of medullary cystic kidneydisease are caused by mutations in either the

MCKD1

or

MCKD2

gene.

17,18

These diseases are also char-acterized by bilaterally shrunken kidneys, cysts re-stricted to the renal medulla, salt wasting, and poly-uria. But unlike nephronophthisis, medullary cystickidney diseases are inherited as autosomal domi-nant traits (Table 1), are clinically milder, and typi-cally first appear in adulthood.

In autosomal dominant polycystic kidney disease,the thousands of large, spherical cysts of varioussizes throughout the cortex and medulla are derivedfrom every segment of the nephron. The tubule wall,which is lined by a single layer of epithelial cells,expands and then rapidly closes off from the tubuleof origin (Fig. 2B).

1

By contrast, in autosomal reces-sive polycystic kidney disease, the smaller, elongat-ed cysts arise as ectatic expansions of collectingducts and maintain contact with their nephron oforigin (Fig. 2C). In nephronophthisis and medul-lary cystic kidney disease, the cysts are restrictedto the corticomedullary border and may be derived

from collecting ducts and distal tubules. Despitethese differences among polycystic kidney diseases,common features control the formation and en-largement of renal cysts.

19

proliferation and apoptosis

A precisely controlled balance between cellular pro-liferation and programmed cell death (apoptosis)is essential for normal growth and differentiationof the kidney and maintenance of normal renalstructure after birth. These fundamental processesare disturbed in polycystic kidneys. In both autoso-mal dominant and autosomal recessive polycystickidney disease, apoptosis is abnormally persistent

20

and can destroy much of the normal renal paren-chyma, thereby allowing cystic epithelia to prolif-erate. The importance of apoptosis has been high-lighted in knockout mice, in which the inactivationof inhibitors of apoptosis (bcl-2 or activating pro-tein 2

b

[AP-2

b

]) causes cystic kidney disease.

21,22

Rodent models of polycystic kidney disease are list-ed in Supplementary Appendix 1 (available withthe full text of this article at www.nejm.org).

The proliferation of renal tubular epithelial cellsceases before birth, but cystic epithelia proliferateabnormally throughout life in patients with auto-somal dominant polycystic kidney disease.

23

More-over, cultured epithelial cells from these patientshave an increased intrinsic capacity for proliferationand survival. Several genetic manipulations thatcause the proliferation of tubular epithelial cells inmice also lead to renal cystic disease

24-27

(see Sup-plementary Appendix 1).

Epidermal growth factor (EGF) has an impor-tant role in the expansion of renal cysts. Epithelialcells from cysts from patients with the autosomaldominant form and from those with the autosomalrecessive form are unusually susceptible to the pro-liferative stimulus of EGF. Moreover, cyst fluidsfrom the former group of patients contain mito-genic concentrations of EGF, and this EGF is se-creted into the lumens of cysts in amounts that caninduce cellular proliferation.

28

The overexpressionand abnormal location of EGF receptors on the api-cal (luminal) surface of cyst-lining epithelia createsa sustained cycle of autocrine–paracrine stimula-tion of proliferation in the cysts

28

(Fig. 3).Genetic experiments in mice have also shown

the importance of the overexpression of EGF recep-tors in the formation of renal cysts,

29

and this workhas led to the development of specific inhibitors ofthe EGF-receptor tyrosine kinase, which have re-

familial nephronophthisis

medullary cystic kidney disease

cell biology



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duced the number of cysts and extended the lifespan of mice with polycystic kidney disease.

30

Thisclass of small-molecule inhibitors of tyrosine ki-nase is now under investigation in phase 1 and 2clinical trials in adults with polycystic kidney dis-ease to determine whether they slow the expansionof cysts and the decline in renal function.

EGF receptors are also expressed in the apicalmembranes of collecting-tubule epithelia in nor-mal fetal kidneys

31

(Fig. 3). Whereas basal EGF re-ceptors in normal adult epithelia are comprised ofhomodimers, the apical EGF receptors consist ofheterodimers of EGF receptor and erb-b2.

31

Theimportance of this EGF-receptor variant, erb-b2, isilluminated by the fact that renal cysts form in trans-genic mice that overexpress

erb-b2

32

and that erb-b2 inhibitors have a protective effect in vitro on cellsfrom patients with autosomal dominant polycystickidney disease. These observations suggest thaterb-b2 inhibitors might have therapeutic value.

Additional growth factors, cytokines, and lipidfactors, as well as adenosine triphosphate (ATP) andcyclic adenosine monophosphate (cAMP) in cystfluids, have proliferative effects on epithelial cellsin vitro.

19,33-35

These factors may stimulate EGF-dependent growth of cysts.

36

secretion

The net reabsorption of fluid in the normal kidneyis brought about by sodium ion gradients estab-lished by the sodium pump (Na

+

/K

+

–ATPase) in thebasolateral tubular cell membrane and by multipleion and fluid transporters and channels in apicaland basolateral sites. In kidneys of patients withpolycystic kidney disease, Na

+

/K

+

–ATPase is abnor-mally located in the apical (luminal) cell membranesof tubular epithelia (Fig. 3)

37

and the Na

+

,K

+

,2Cl

¡

symporter is misplaced to the basal surface of theepithelia.

38

Molecular studies of the

a

and

b

subunits ofthe Na

+

/K

+

–ATPase complex have shown that nor-mal adult kidneys contain

a

1

b

1 complexes, which

Normal Nephron

Cyst Formation in AutosomalDominant Polycystic Kidney Disease

Cyst Formation in AutosomalRecessive Polycystic Kidney Disease

Loop ofHenle

A

B

C

Proximaltubule

Collectingtubule

Figure 2. Mechanisms of Cyst Formation in Polycystic Kidney Disease.

Cysts originate as expansions of the renal tubule (Panel A). In autosomal dominant polycystic kidney disease, cystic outpushings arise in every tubule segment and rapidly close off from the nephron of origin (Panel B). By contrast, in autosomal recessive polycystic kidney disease, cysts are derived from collecting tubules, which remain connected to the nephron of origin (Panel C).



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are located in the basolateral region of the tubule,whereas the kidneys of patients with polycystic kid-ney disease contain

a

1

b

2 complexes in the apicalmembrane

39

(Fig. 3). In the normal fetus, Na

+

/K

+

–ATPase is also composed of

a

1

b

2 complexes andoccurs on the apical membranes of renal tubules.

40

It seems that in autosomal dominant polycystickidney disease, a failure to down-regulate the tran-scription of the

b

2 isoform after birth facilitates theerroneous placement of Na

+

/K

+

–ATPase in the api-cal membrane.

Additional transport-related features of cysts in-clude the presence of aquaporin 1 or aquaporin 2water channels in cyst epithelia from patients withautosomal dominant polycystic kidney disease andof aquaporin 2 alone in cysts from patients with theautosomal recessive form.

41

The high levels of ATPreleased by apical membranes in patients with theautosomal dominant form may further exacerbatesecretion.

42

Intracellular cAMP levels are also im-

portant regulators of secretion in cysts and regulatethe cystic fibrosis transmembrane conductance reg-ulator chloride channels in the apical membranesof cystic epithelia from patients with autosomaldominant polycystic kidney disease.

43

cell–matrix interactions

Abnormalities in the basement-membrane struc-ture, interstitial matrix composition, the levels ofmatrix metalloproteases and their inhibitors, andthe expression of integrin receptors occur in patientswith polycystic kidney disease.

40

Thickened base-ment membranes, alterations in matrix composi-tion, and abnormal numbers of integrin receptorsare frequent in autosomal dominant as well as au-tosomal recessive polycystic kidney disease andjuvenile nephronophthisis. These alterations causemarked functional disturbances. For example, epi-thelia from patients with autosomal dominant poly-cystic kidney disease are more adherent to matrixes

Figure 3. Polarization of Epidermal Growth Factor Receptor (EGFR) and Na

+

/K

+

–ATPase in Epithelium from a Normal Fetus, a Normal Adult, and a Patient with Polycystic Kidney Disease.

Fetal and epithelial cells and epithelia from patients with polycystic kidney disease express heterodimeric complexes of EGFR and erb-b2 as well as heterodimeric complexes of

a

1

b

2 Na

+

/K

+

–ATPase at apical-cell membranes. In normal adults tubular epithelia express homodimeric complexes of epidermal growth factor receptor and homodimeric complexes of

a

1

b

1 Na

+

/K

+

–ATPase at basolateral membranes.



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made up of collagen type I or IV than are normalepithelia and have decreased migratory capacitiesagainst growth factor gradients.44,45 Such defectsmay impair the cell movements required for mor-phogenesis of the kidney.

Genetic experiments in mice have shown thatinactivation of several matrix adhesion receptorsand focal adhesion complex–associated proteinscauses the formation of cysts.46-49 Similarly, over-expression of polycystin-1 or b-catenin (Wnt) caus-es cysts.50,51 The migratory defect of epithelial cellsfrom patients with autosomal dominant polycystickidney disease can be reversed by inhibitors of theWnt pathway.45 These molecules may have poten-tial therapeutic applications.

polarityThe normal adult nephron is a segmented struc-ture lined by at least 15 distinct types of highly po-larized epithelia. The polarized distribution of en-zymes, ion transporters, channels, pores, growthfactor, and matrix receptors facilitates normal vec-torial function (directional transport) and the con-trol of cell division, differentiation, and maturation.In autosomal dominant and autosomal recessivepolycystic kidney disease, alterations in the polarityof membrane proteins include aberrant location ofNa+/K+–ATPase, EGF receptors, cathepsin B, ma-trix metalloproteinase 2, and E-cadherin in the api-cal-cell membrane rather than the basolateral mem-brane.19,52 Polarization of proteins occurs duringthe maturation of nephrons in utero and proceedsby means of the regulated switching of gene expres-sion. Persistent expression of fetal forms of Na+/K+–ATPase and EGF receptors suggest the pres-ence of a block in the maturation program.28,31,39,40

The protein encoded by PKD1, polycystin-1, hasdefects in polarity and trafficking in patients withautosomal dominant polycystic kidney disease. Innormal renal epithelia, polycystin-1 is confined tolateral cell membranes at sites of cell–cell adhesion(adherens junctions) and cell–matrix contacts (fo-cal adhesions), whereas in cystic epithelia, most ofthis protein is intracellular.53

signal transductionMany intracellular signal-transduction pathwayshave been implicated in the etiologic process ofpolycystic kidney disease. The PKD1, PKD2, andNPH1 gene products can themselves activate intra-cellular signaling cascades that regulate cell prolif-eration, migration, and differentiation35,54,55 (Fig.

4). Integration of these pathways is essential for thecell movements underlying morphogenesis and theformation and maintenance of renal tubules withcorrect luminal diameters. Polycystins initiate thesepathways through interactions with several pro-teins at the cell–cell adherens junctions and cell–matrix focal adhesion complexes. Loss of the focaladhesion function in mutant polycystin-1 resultsin the failure to recruit the focal adhesion kinasein patients with autosomal dominant polycystickidney disease (Fig. 5), and mutation of nephro-cystin in nephronophthisis causes the formationof cysts.15,46 Additional regulation of the functionof polycystins occurs by means of G proteins,56

phosphorylation by serine kinases57,58 or tyrosinekinases,57 dephosphorylation by receptor proteintyrosine phosphatases,59 and the intracellular sec-ond messengers calcium and cAMP.60-62

Current evidence suggests that complex pat-terns of signaling from polycystins, intracellularsecond messengers, and growth factors coordinatethe regulation of the proliferation, differentiation,and morphogenesis of renal tubular cells throughinteractions with protein complexes linked to theactin cytoskeleton, intracellular signaling cascades,and the regulation of gene transcription (Fig. 4).Perturbations of these regulatory mechanisms bymutations in PKD1, PKD2, or NPH1 disrupt theseprocesses15,63-65 (Fig. 4).

ciliaThe principal cells of the renal collecting tubulehave a solitary central cilium, the function of whichis obscure. Intriguingly, two mutant mouse strainswith autosomal recessive polycystic kidney disease(Tg737 and cpk) have abnormal ciliary structureor function, and their encoded proteins (polarisand cystin) colocalize with polycystins in collecting-tubule cilia.66,67 However, it is not known whetherthese abnormalities apply to autosomal recessivepolycystic kidney disease in humans, which involvesa mutant PKHD1 gene. Genetic studies in a worm(Caenorhabditis elegans) and functional studies in cellculture and a Pkd-1 mutant mouse suggest a senso-ry role for the cilium in autosomal dominant poly-cystic kidney disease.68-70

pkd genes and mutationsA wide range of mutations in PKD1 or PKD2 cancause autosomal dominant polycystic kidney dis-

molecular biology




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ease. These mutations are spread across the entiresequence of these genes and include deletions, in-sertions, and frame shifts and splicing, nonsense,missense, and point mutations.64 In kindreds,most mutations encode a truncated protein and areunique to a single family. PKD1, a large gene with46 exons, encodes a 14.5-kb transcript (Table 1).The existence of additional PKD1-like homologous

genes upstream of the 5' region of PKD1 compli-cates mutation analysis considerably. More than100 mutations of PKD1 have been identified. Bycontrast, PKD2, a simpler 15-exon gene, encodes asmaller 5.6-kb transcript (Table 1). More than 75mutations of PKD2 have been identified, again main-ly of the inactivating type.71

Patients with autosomal dominant polycystic

Figure 4. The Function of Polycystin-1.

Polycystin-1 complexes are found at the cell–matrix interface, cell–cell contacts, and luminal cilium, where they are thought to function as sensors of the extracellular environment and interact with proteins of the cell membrane and actin and tubulin cytoskeleton and transduce signals by means of intracellular phosphorylation cascades to regulate gene transcription in the nucleus. Polycystin-1 interacts with polycys-tin-2, a2b1 integrin, receptor protein tyrosine phosphatase (RPTP), and E-cadherin at cell membranes, in focal adhesions, at adherens junc-tions, and in collecting-duct central cilia. On the intracellular face, polycystin-1 interacts with the focal adhesion proteins talin (TAL), paxillin (PAX), vinculin (VINC), focal adhesion kinase (FAK), c-src (SRC), p130-cas (CAS), nephrocystin (NPH1), the proline-rich kinase pyk-2 (Py), and tensin (TEN) and with the adherens junction proteins b-, a-, and g-catenin and E-cadherin, which may regulate cell–matrix focal adhesion and cell–cell adhesion, respectively. Polycystin-2 and transient receptor potential calcium-channel 1 (TRPC-1) can facilitate calcium influx, which may act as an intracellular second messenger. The second messenger cyclic AMP (cAMP), as well as G proteins (G), may regulate the function of polycystins through interactions with the polycystin-1 C-terminal at defined sites. The polycystin-1 C-terminal contains sites for phosphorylation on serines (by protein kinases A and X) and on tyrosines (by c-src and focal adhesion kinase), as well as proline-rich src homology 3 (SH3) and putative WW sites. Signal-transduction cascades induced by the polycystin complex include those of the Wnt pathway (by means of b-catenin and T-cell [TCF] and lymphoid-enhancing [LEF] transcription factors), the focal adhesion pathway (by means of MAP kinase [MAPK], JUN kinase [JNK], and activating protein 1 [AP-1] transcription), and the JAK2–STAT1 pathways, suggesting transcriptional regulation of proliferation, apoptosis, epithelial differentiation, polarity, adhesion, migration, cell shape, and tubular diameter, which are all components of renal morphogenesis.

SRC

Actin

Lumen

Actin

Polycystin-1

RPTP

Integrin

Polycystin-1RPTP

Polycystin-2

Polycystin-2

TRPC-1

Cell–celladherensjunction

Cilium

Ca2+

Ca2+

Cystin

T737/Polaris

Tubulin

Cell–matrixfocal adhesion

Nucleus

Polycystin-1

E-cadherin

cAMPb

a

g

Gene transcription

TCF/LEF AP-1 STAT-1

JAK2

MAPKJNK

b-catenin

G

G

py

Polycystin-2

TAL

PAXCAS

FAK

TEN

NPH1VINC





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kidney disease are heterozygotes, having inherit-ed one mutant and one normal (wild-type) alleleof PKD1. A “two-hit” mechanism has been proposedto explain how cysts develop.72 This mechanismrequires not only a germ-line mutation of PKD1 orPKD2 but also an additional somatic mutation in thewild-type gene to initiate the formation of cysts. Al-though such second hits (point mutations) do in-deed occur within individual cysts, the frequenciesare low (17 percent in PKD1 and up to 43 percent inPKD2),73 and polycystin protein is seen in most cystepithelial cells of kidneys from patients with auto-somal dominant polycystic kidney disease. The evi-dence suggests that the somatic (point) mutationsmust either allow transcription of the mutated wild-type allele or block production of polycystin-1 orpolycystin-2.

Although complete loss of PKD1 or PKD2 clearlycauses massive formation of renal cysts74 (Table 2),there is also a gene dose effect, since either too littlePKD1 (complete absence or haploinsufficiency) ortoo much PKD1 (transgenic overexpression) causescyst formation.50,77

The gene for autosomal recessive polycystickidney disease, PKHD1, has 67 exons and encodes

a large 16.2-kb transcript. Many splice variants ex-ist, and several different mutations have been de-tected throughout the entire coding region. Mostmutations predict the translation of a truncated pro-tein (Table 2).

The juvenile nephronophthisis gene, NPH1,has 20 exons and encodes a small 4.5-kb transcript.Seventy to 80 percent of affected patients have ho-mozygous deletions, whereas the remainder areheterozygotes. A variety of inactivating, nonsense,splice-site, and point mutations have been identi-fied (Table 2).15

polycystic kidney disease proteinsPolycystin-1Polycystin-1 is a large (>460 kD) membrane proteinwith a long extracellular N-terminal, 11 transmem-brane domains, and a short intracellular C-termi-nal.75,76 Its extracellular portion contains structuralmotifs for binding matrix and cell-membrane pro-teins in the environment of renal tubular epithelia.The intracellular portion of the protein has manysites for phosphorylation and responses to regula-tors of signal transduction63 (Fig. 1 and 4). Polycys-tin-1 interacts and forms complexes with many oth-

Figure 5. Polycystin-1–Focal Adhesion Complex.

As shown in Panel A, in normal renal epithelia, polycystin-1 interacts in a multiprotein complex with integrins and focal adhesion proteins, in-cluding the focal adhesion kinase (FAK). As shown in Panel B, in epithelia from patients with autosomal dominant polycystic kidney disease, although polycystin-1–focal-adhesion complexes are formed, they lack FAK. TAL denotes talin, PAX paxillin, VINC vinculin, CAS p130-cas, SRC c-src, TEN tensin, and NPH1 nephrocystin.

NormalA Autosomal Dominant Polycystic Kidney DiseaseB

Polycystin-1 Polycystin-1

Integrina

ba

b

Integrin

Actin

TALPAX

SRCCAS

FAKVINC

TEN

NPH1

Actin

Focal adhesioncomplex

TALPAX

SRCCAS

VINC

TEN

NPH1

Focal adhesioncomplex





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er proteins in the plane of the cell membrane and onthe intracellular face of the membrane that links theextracellular environment to the intracellular actincytoskeleton (Fig. 4).

Polycystin-2The PKD2-encoded protein polycystin-2 is a 110-kDmembrane protein with six transmembrane do-mains and intracellular N- and C-terminal domainswith structural similarities to voltage-activatedL-type calcium and sodium channels.4 Structuraland functional analyses place polycystin-2 in thetransient receptor potential family of channel pro-teins together with the newly identified polycys-tin-like calcium channels PKDL and PKD2L2.78

Although polycystin-2 can function as a nonselec-tive cation channel that is permeable to calcium,there is uncertainty whether it functions alone oronly when it forms a complex with polycystin-1 atthe cell membrane or in the endoplasmic reticu-lum.61,79-81

FibrocystinAlthough little is known about the large (447-kD)protein involved in autosomal recessive polycystickidney disease, fibrocystin (also known as polyduc-tin), its structure suggests that it is an integral mem-brane receptor with extracellular protein-interactionsites and intracellular phosphorylation sites11 (Fig.1). Disease-causing mutations of PKHD1 truncatethe C-terminal of fibrocystin, removing or inacti-vating putative signaling sites. Fibrocystin is abun-dant in fetal-kidney collecting ducts but absent inthe kidneys of some patients with autosomal re-

cessive polycystic kidney disease. Taken together,these properties suggest that like polycystin-1, fi-brocystin may act as a membrane receptor, inter-acting with extracellular protein ligands and trans-ducing intracellular signals to the nucleus.

NephrocystinUnlike the polycystins and fibrocystin, nephro-cystin is a wholly intracellular small (83-kD) pro-tein. It binds to focal adhesion proteins, includingp130cas and tensin.15 The polycystins and nephro-cystin probably interact with focal-adhesion-com-plex proteins, in which phosphorylation activatesintracellular signaling pathways82 (Fig. 4). Evi-dence supports the existence of a central role forthe control of polycystin–nephrocystin–adhesioncomplexes at focal adhesion points in the cell ma-trix for the regulation of renal tubule geometry.

functions of polycystinsA wide range of analyses have led to the conclusionthat polycystin-1 functions as a membrane recep-tor, capable of binding and interacting with manyproteins, carbohydrates, and lipids83,84 and elicit-ing intracellular responses through phosphoryla-tion pathways,57,85 and that polycystin-2 acts as acalcium-permeable channel.65 Polycystin-1 is foundat three major renal tubular cell sites: the cell–matrixfocal adhesion complex, cell–cell junctions, and thecilium, each of which links the extracellular envi-ronment of the cell membrane to the intracellularactin–tubulin cytoskeleton (Fig. 4). Through mul-tiple interactions with other proteins and modifi-cations by phosphorylation, polycystin complexes

Table 2. Molecular Mechanisms of Polycystic Kidney Disease.

Type of Disease Cause Reference Molecular Mechanisms

Autosomal dominant polycystic kidney disease

Mutation in PKD1Decrease in functional

polycystin-1

Mutation in PKD2Decrease in functional

polycystin-2

European PK Consortium3,75

Hughes et al.76

Mochizuki et al.4

Polycystin-1 is a membrane mechanoreceptor-like protein that forms multiprotein complexes at focal adhesions, cell–cell junctions, and cilia. Interactions with the extracellular environment lead to intracellular signaling and transcriptional regulation of proteins that regulate renal morphogenesis and differentiation, including control of renal tubule diameter through effects on epithelial-cell proliferation, adhesion, and migration.

Polycystin-2 is a nonselective cation, calcium-permeable membrane channel that interacts with the polycystin-1 complex and may reg-ulate transport of polycystin-1 from the endoplasmic reticulum to the plasma membrane.

Autosomal recessive polycystic kidney disease

Mutation in PKHD1Loss of functional

fibrocystin

Ward et al.,11 Hildebrandtet al.48

Fibrocystin is a receptor-like membrane protein with putative extra-cellular-matrix–interaction domains as well as intracellular signal-ing sites.

Juvenile nephron-ophthisis

Mutation in NPH1Loss of functional

nephrocystin

Antignac et al.,14

Hildebrandt and Otto15

Nephrocystin is an intracellular protein that interacts with the focal adhesion complex, the cilium, and tyrosine signaling molecules.





161

stimulate intracellular signaling cascades that in-fluence gene transcription.54,63,86 The evidencesuggests that the polycystin complex acts as amechanosensor, receiving signals from the extra-cellular matrix (by means of focal adhesions), adja-cent cells (through cell junctions), and tubule lu-men (through cilia), and transduces them intocellular responses that regulate proliferation, ad-hesion, migration, differentiation, and maturationessential for the control of the diameter of renal tu-bules and kidney morphogenesis.35,87

Autosomal dominant polycystic kidney disease isa developmental disorder. Multiple renal cysts oc-cur in utero,88 mice with homozygous targeted dis-ruptions of the pkd1 or pkd2 gene die in utero orperinatally,49 and many fetal genes, proteins, andfunctions are expressed in affected patients.31,39

Polycystin-1 is developmentally regulated. Thereare high levels of the protein in fetal ureteric-budand collecting-tubule cells and low levels in adultkidneys.53,89-92 In kidneys from 8-to-16-week-oldfetuses, polycystin-1 is predominantly found in ba-sal-membrane focal adhesions of migrating epithe-lia derived from the ureteric bud. Later in gestationand in the adult kidney, expression of polycystin-1is down-regulated and restricted to medullary col-lecting tubules in lateral cell–cell adherens junc-tions.63 Polycystin-1 is important in the regulationof adhesion, migration, and branching elongationof the ureteric bud during renal development. Mu-tations in PKD1, PKD2, or NPH1 disrupt this finelycoordinated process and lead to the formation ofcysts.87,93

Some genetic factors that influence the rate of pro-gression of autosomal dominant polycystic kidneydisease to end-stage renal failure have been identi-

fied, including the nature of the inherited muta-tion. Patients with mutations in PKD2 (type II) havea slower rate of disease progression than patientswith mutations in PKD1 (type I),67 mutations in the5' portion of PKD1 lead to the early onset of a rapid-ly progressive disease,94,95 and the presence of bothPKD1 and PKD2 mutations is predictive of severedisease.8 Associated conditions such as hyperten-sion also increase the severity of the disease, possi-bly through effects of modifier genes, as suggestedby the earlier onset of end-stage renal failure inpatients with autosomal dominant polycystic kid-ney disease and angiotensin-converting–enzymedeletion polymorphisms.96,97 Another acceleratorof progression is interstitial fibrosis, whether it iscaused by the proliferation of fibroblasts, inflam-matory cytokines, toxic and traumatic insults, ordietary additives. The recent availability of rodentmodels with targeted mutations in pkd1 and pkd2or with spontaneous mutations syntenic to muta-tions in NPH3 (Pcy mouse)16 and PKHD1 (Pck rat)11

and well-characterized primary and conditionallyimmortalized renal epithelial cell cultures from nor-mal human fetal and adult nephron segments, aswell as cyst lining epithelia from patients with au-tosomal dominant polycystic kidney disease andautosomal recessive polycystic kidney disease,98

should speed the development of genetic, pharma-cologic, or dietary interventions.

Because autosomal dominant polycystic kidneydisease is slowly progressive, there is a window ofopportunity to treat the disease by retarding cysticexpansion. However, new methods of assessing re-nal decline, such as monitoring the reduction in thenumbers and size of cysts, must be developed andaccepted by regulatory agencies. The most promis-ing example of potential therapy is the EGF-recep-tor tyrosine kinase inhibitors. Treatment of the morerapidly progressing forms of polycystic kidney dis-eases may present a greater challenge, since treat-ment will have to occur during the developmentalperiod. In these cases, other tyrosine and serine ki-nase targets as well as gene-therapy approaches mayprove optimal.

developmental regulation

and programming

prospects for prognosis

and therapy

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