The vasculopathy of autosomal dominant polycystic kidney disease: Insights from animal models

Abstract

A 37-year-old white man with autosomal dominant polycystic kidney disease (ADPKD) was admitted to Boston's Beth Israel Hospital with sudden severe headache of two-hour duration. He was unconscious on admission. Emergency angiography revealed a ruptured 15 mm cerebral aneurysm. Emergency surgery to clip the aneurysm was unsuccessful, and the patient died 36 hours after admission. His serum creatinine was 3.2 mg/dL on admission; the rest of his laboratory values were within normal limits. A request for an autopsy was denied. At age 20, the patient and his then 15-year-old sister had abdominal ultrasound examinations that revealed bilateral renal cysts, consistent with the diagnosis of ADPKD. At age 32, the patient had a sudden, relatively severe, acute myocardial infarction (MI). Cardiac catheterization revealed three-vessel disease, and he subsequently underwent a triple coronary artery bypass operation. Throughout his medical course, the patient's blood pressure was in the 120/80 to 140/80 mm Hg range while he was taking lisinopril, 10 mg/day, which was started after his MI. The patient's mother has ADPKD and end-stage renal disease, and she is on hemodialysis. She recently underwent unsuccessful renal transplantation. There is no known family history of cerebral aneurysms. However, the mother had two cerebrovascular accidents and recovered from both. The patient's father had an MI at age 32, but he lived to age 64. A paternal uncle also died at an early age of an MI. The patient's younger sister was later screened for cerebral aneurysms and the test was negative. The patient's two young children have not been screened for ADPKD. DR. M. AMIN ARNAOUT (Chief, Renal Unit, Massachusetts General Hospital, and Professor of Medicine, Harvard Medical School, Boston, Massachusetts, USA): This case represents one of the most feared outcomes in a patient with ADPKD, the fatal rupture of a cerebral aneurysm. It took place in a young patient with well-controlled blood pressure, moderate renal dysfunction, and no family history of aneurysms. This case also raises issues relating to the spectrum of the vascular lesions in ADPKD, and the indications for prospective imaging studies in asymptomatic patients with no family history. Two recent Nephrology Forums have expertly addressed the extrarenal manifestations and complications of ADPKD1.Perrone R.D. Extrarenal manifestations of ADPKD.Kidney Int. 1997; 51: 2022-2036Abstract Full Text PDF PubMed Scopus (54) Google Scholar,2.Watson M.L. Complications of polycystic kidney disease.Kidney Int. 1997; 51: 353-365Abstract Full Text PDF PubMed Scopus (16) Google Scholar. In today's presentation, I will provide an overview of the progress made in the molecular genetics and pathogenesis of ADPKD, focusing on new insights into the genesis of the vasculopathy that were derived from animal models of the disease. Autosomal dominant polycystic kidney disease, the most common inherited renal disease in patients on hemodialysis, is one of the most common genetic diseases in humans. Bilateral renal cysts are the cardinal feature of ADPKD, but cysts in other ductal organs, such as the liver and pancreas, are common. Renal cysts arise from fewer than 1% of nephrons and enlarge throughout the lifetime of an individual, culminating in end-stage renal disease in approximately 50% of affected individuals by age 50. As today's tragic case illustrates, ADPKD is also a disease of blood vessels. Cardiovascular abnormalities include vascular aneurysms that sometimes recur3.Chauveau D. Sirieix M.E. Schillinger F. Legendre C. Grünfeld J.P. 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Clustering of intracranial aneurysms has been described in several ADPKD families, with the incidence of aneurysms rising to approximately 25% in asymptomatic patients in some families14.Huston J.D. Torres V.E. Sulivan P.P. Offord K.P. Wiebers D.O. Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 1993; 3: 1871-1877PubMed Google Scholar,15.Ruggieri P.M. Poulos N. Masaryk T.J. Ross J.S. Obuchowski N.A. Awad I.A. Braun W.E. Nally J. Lewin J.S. Modic M.T. Occult intracranial aneurysms in polycystic kidney disease: Screening with MR angiography.Radiology. 1994; 191: 33-39Crossref PubMed Scopus (129) Google Scholar. Marked sclerosis of preglomerular vessels also has been seen, even in early cases when blood pressure and serum creatinine are still normal16.Zeier M. Fehrenbach P. Geberth S. Mohring K. Waldherr R. Ritz E. 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Long-term cardiovascular morbidity and mortality in autosomal dominant polycystic kidney disease patients after renal transplantation.Transplantation. 1994; 57: 73-81Crossref PubMed Scopus (53) Google Scholar. Autosomal dominant polycystic kidney disease is caused by mutations in two genes, PKD1 and PKD2, which are mapped to chromosomes 16p13.3 and 4ql3-p23, respectively24.Reeders S.T. Breuning M.H. Davies K.E. Nicholls R.D. Jarman A.P. Higgs D.R. Pearson P.L. Weatherall D.J. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16.Nature. 1985; 317: 542-544Crossref PubMed Scopus (528) Google Scholar,25.Kimberling W.J. Kumar S. Gabow P.A. Kenyon J.B. Connolly C.J. Somlo S. Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q14-q23.Genomics. 1993; 18: 467-472Crossref PubMed Scopus (279) Google Scholar. Mutations in the PKD1 gene are responsible for 85% to 90% of all cases of ADPKD; mutations in PKD2 cause the disease in most of the remaining patients. In humans and mice, PKD1 is closely linked to TSC2, a gene responsible for a major form of tuberous sclerosis26.The European Chromosome 16 Tuberous Sclerosis Consortium Identification and characterization of the tuberous sclerosis gene on chromosome 16.Cell. 1993; 75: 1305-1315Abstract Full Text PDF PubMed Scopus (1423) Google Scholar. In patients with mutations in PKD2, progression to end-stage renal failure is delayed by an average of 10 years, in association with fewer renal cysts and milder hypertension. In a small number of families, a third, yet-to-be-characterized gene, has been implicated27.Ariza M. Alvarez V. Marin R. Aguado S. Lopez-Larrea C. Alvarez J. Menendez M.J. Coto E. A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16q) or PKD2 (4q) genes.J Med Genet. 1997; 34: 587-589Crossref PubMed Scopus (56) Google Scholar. The ∼50 kb PKD1 gene contains 46 exons encoding an ∼14 kb mRNA. Seventy percent of the gene (from exon 1 to intron 34) is replicated in at least three homologous genes (HG) at an adjacent site on chromosome 16pl3.1. Although no evidence has shown that any of these homologous genes are translated into protein products28.Ong A.C. Harris P.C. Davies D.R. Pritchard L. Rossetti S. Biddolph S. Vaux D.J. Migone N. Ward C.J. Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue.Kidney Int. 1999; 56: 1324-1333Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, these genes, through gene conversion, could promote mutations in PKD129.Watnick T.J. Gandolph M.A. Weber H. Neumann H.P. Germino G.G. Gene conversion is a likely cause of mutation in PKD1.Hum Mol Genet. 1998; 7: 1239-1243Crossref PubMed Scopus (78) Google Scholar. A second mechanism for increased mutability of human PKD1 might relate to the presence of long polypurine·polypyrimidine tracts in two introns capable of forming multiple non-B-DNA structures30.Blaszak R.T. Potaman V. Sinden R.R. Bissler J.J. DNA structural transitions within the PKD1 gene.Nucleic Acids Res. 1999; 27: 2610-2617Crossref PubMed Scopus (47) Google Scholar. These two features, the 5′ duplications31.Olsson P. Lohning C. Horsley S. Kearney L. Harris P. Frischauf A. The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy gene.Genomics. 1996; 34: 233-235Crossref PubMed Scopus (31) Google Scholar and the polypurine-polypyrimidine tracts32.Piontek K.B. Germino G.G. Murine Pkd1 introns 21 and 22 lack the extreme polypyrimidine bias present in human PKD1.Mamm Genome. 1999; 10: 194-196Crossref PubMed Scopus (12) Google Scholar, are lacking in the mouse homologue of PKD1 (Pkd1), in which no spontaneous mutations in PKD1 are known to occur. The majority of PKD1 mutations33.Peral B. Gamble V. Strong C. Ong A. Sloane-Stanley J. Zerres K. Winearls C. Harris P. Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.Am J Hum Genet. 1997; 60: 1399-1410Abstract Full Text PDF PubMed Scopus (94) Google Scholar, however, are not accounted for by either of these two features. In addition, the age-dependent increase in mutant frequency in primary cell clones isolated from the human renal cortex has not been observed in mice. This suggests a more general resistance to mutability in mouse cells34.Martin G.M. Ogburn C.E. Colgin L.M. Gown A.M. Edland S.D. Monnat Jr, Rj Somatic mutations are frequent and increase with age in human kidney epithelial cells.Hum Mol Genet. 1996; 5: 215-221Crossref PubMed Scopus (143) Google Scholar. The mouse homologue of PKD1 (Pkd1) maps to mouse chromosome 1731.Olsson P. Lohning C. Horsley S. Kearney L. Harris P. Frischauf A. The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy gene.Genomics. 1996; 34: 233-235Crossref PubMed Scopus (31) Google Scholar. The ∼68 kb human PKD2 gene contains 15 exons and encodes a ∼5.4 kb transcript31.Olsson P. Lohning C. Horsley S. Kearney L. Harris P. Frischauf A. The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy gene.Genomics. 1996; 34: 233-235Crossref PubMed Scopus (31) Google Scholar. It does not contain unusual features similar to those present in the human PKD1 gene. The mouse homologue of PKD2 (Pkd2) maps to mouse chromosome 535.Wu G. Mochizuki T. Le T.C. Cai Y. Hayashi T. Reynolds D.M. Somlo S. Molecular cloning, cDNA sequence analysis, and chromosomal localization of mouse Pkd2.Genomics. 1997; 45: 220-223Crossref PubMed Scopus (28) Google Scholar. Polycystin-1 and polycystin-2, the proteins encoded by PKD1 and PKD2, respectively, belong to a family of proteins, five members of which have been described to date Figure 1. Polycystin-1 is a 4302 amino acid 11-pass plasma membrane protein with an apparent molecular mass greater than 450 kD, and multiple potential glycosylation sites36.Consortium TIPKD Polycystic kidney disease: The complete structure of the PKD1 gene and its protein.Cell. 1995; 81: 289-298Abstract Full Text PDF Scopus (603) Google Scholar. Mouse polycystin-1 is 4298 amino acids long, with 79% amino acid identity to human polycystin-137.Lohning C. Nowicka U. Frischauf A. The mouse homolog of PKD1: Sequence analysis and alternative splicing.Mamm Genome. 1997; 8: 307-311Crossref PubMed Scopus (35) Google Scholar. 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The sea urchin sperm receptor for egg jelly is a modular protein with extensive homology to the human polycystic kidney disease protein, PKD1.J Cell Biol. 1996; 133: 809-817Crossref PubMed Scopus (211) Google Scholar, which mediates the acrosomal reaction, a calcium-channel-gated event, upon ligand binding. In polycystin-1, the REJ domain is followed by 11 putative transmembrane (TM) regions. The C-tail contains a predicted coiled-coil region that interacts in vitro with a proposed coiled-coil region in polycystin-240.Qian F. Germino F.J. Cai Y. Zhang X. Somlo G.G. PKD1 interacts with PKD2 through a probable coiled-coil domain.Nat Genet. 1997; 16: 179-183Crossref PubMed Scopus (536) Google Scholar. These features suggest potential roles for polycystin-1 in cell-cell and cell-matrix interactions as well as in regulation of ion transport either directly or through its association with polycystin-2, a putative ion channel41.Mochizuki T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides A. Kimberling W.J. Breuning M.H. Deltas C.C. Peters D.J.M. Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1103) Google Scholar. The last six TM segments of polycystin-1 are homologous to the six TM regions found in each of the other four family members. Homology also extends to the REJ domain found in polycystin-REJ. Polycystin-2 is 968 amino acids long, with an apparent molecular mass of approximately 110 kD41.Mochizuki T. Wu G. Hayashi T. Xenophontos S.L. Veldhuisen B. Saris J.J. Reynolds D.M. Cai Y. Gabow P.A. Pierides A. Kimberling W.J. Breuning M.H. Deltas C.C. Peters D.J.M. Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1103) Google Scholar. Its N- and C-termini are cytoplasmic, and it has six (S1-S6) transmembrane segments with homology to the C-terminal six TM region in polycystin-1, to the α-subunit of a large group of voltage-activated calcium and sodium channels, and to the store-operated transient receptor potential channel (TRPC) subunits, where homology is limited to the S5-6 region42.Tsiokas L. Arnould T. Zhu C. Kim E. Walz G. Sukhatme V.P. Specific association of the gene product of PKD2 with the TRPC1 channel.Proc Natl Acad Sci USA. 1999; 96: 3934-3939Crossref PubMed Scopus (257) Google Scholar. The S2-S5 and part of the linker region between S5 and S6 interact with TRPC142.Tsiokas L. Arnould T. Zhu C. Kim E. Walz G. Sukhatme V.P. Specific association of the gene product of PKD2 with the TRPC1 channel.Proc Natl Acad Sci USA. 1999; 96: 3934-3939Crossref PubMed Scopus (257) Google Scholar. The polycystin-2 C-tail contains three functional regions, one involved in localization to the endoplasmic reticulum43.Cai Y. 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Kimberling W.J. Breuning M.H. Deltas C.C. Peters D.J.M. Somlo S. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1103) Google Scholar. Mouse polycystin-2 is 966 amino acids long, with 91% identity to human polycystin-235.Wu G. Mochizuki T. Le T.C. Cai Y. Hayashi T. Reynolds D.M. Somlo S. Molecular cloning, cDNA sequence analysis, and chromosomal localization of mouse Pkd2.Genomics. 1997; 45: 220-223Crossref PubMed Scopus (28) Google Scholar. Three additional human genes, PKDL, PKDREJ, and PKD2L encode other polycystins. All three respective proteins (polycystin-L, polycystin-REJ, and polycystin-2L) are homologous to polycystin-1 and -2 in the putative ion transporting six-pass segment44.Nomura H. Turco A.E. Pei Y. Kalaydjieva L. Schiavello T. Weremowicz S. Ji W. Morton C.C. Meisler M. Reeders S.T. Zhou J. 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It encodes a 2253 amino acid protein and shows approximately 45% similarity to polycystin-1 (corresponding to the predicted TM region and the REJ module) and to polycystin-2 (corresponding to the six TM region)48.Hughes J. Ward C.J. Aspinwall R. Butler R. Harris P.C. Identification of a human homologue of the sea urchin receptor for egg jelly: A polycystic kidney disease-like protein.Hum Mol Genet. 1999; 8: 543-549Crossref PubMed Scopus (106) Google Scholar. PKD2L2 (accession AF118125), located on chromosome 5q3, encodes a protein of 613 amino acids and is approximately 65% similar to polycystin-2, but it appears to lack the EF hand and coiled-coil regions. PKDL, PKDREJ, and PKD2L are not linked to ADPKD in families that show no clear linkage to either the PKD1 or PKD2 locus44.Nomura H. Turco A.E. Pei Y. Kalaydjieva L. Schiavello T. Weremowicz S. Ji W. Morton C.C. Meisler M. Reeders S.T. Zhou J. Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects.J Biol Chem. 1998; 273: 25967-25973Crossref PubMed Scopus (131) Google Scholar, 45.Wu G. Hayashi T. Park J.H. Dixit M. Reynolds D.M. Li L. Maeda Y. Cai Y. Coca-Prados M. Somlo S. Identification of PKD2L, a human PKD2-related gene: Tissue-specific expression and mapping to chromosome 10q25.Genomics. 1998; 54: 564-568Crossref PubMed Scopus (88) Google Scholar, 47.Veldhuisen B. Spruit L. Dauwerse H.G. Breuning M.H. Peters D.J.M. Genes homologous to the autosomal dominant polycystic kidney disease genes (PKD1 and PKD2).Eur J Hum Genet. 1999; 7: 860-872Crossref PubMed Scopus (63) Google Scholar. Identifying mutations in PKD1 is complicated by the presence of the homologous genes. Screening for mutations in ADPKD patients therefore was initially limited to the 3′ single copy region of the gene, and 35 mutations have so far been described in this segment which represents approximately 20% of the gene [reviewed in49.Harris P.C. Autosomal dominant polycystic kidney disease: Clues to pathogenesis.Hum Mol Genet. 1999; 8: 1861-1866Crossref PubMed Scopus (63) Google Scholar. Using a variety of techniques, including the protein truncation test50.Roelfsema J.H. Spruit L. Saris J.J. Chang P. Pirson Y. van Ommen G.J. Peters D.J. Breuning M.H. Mutation detection in the repeated part of the PKD1 gene.Am J Hum Genet. 1997; 61: 1044-1052Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, long-range PCR (in which one of the primers is anchored in the single-copy region33.Peral B. Gamble V. Strong C. Ong A. Sloane-Stanley J. Zerres K. Winearls C. Harris P. 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Recently, mutational analysis of renal cyst-derived DNA of a patient with a known germline mutation in PKD1 revealed som