Kidney Disease：PKD1 (polycystic Kidney Disease 1)
Mar 16, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
Part Ⅰ：Overexpression of PKD1 Causes Polycystic Kidney Disease
Caroline Thivierge, Almira Kurbegovic, Martin Couillard, Richard Guillaume, Olivier Coté, and Marie Trudel
ADPKD (autosomal dominant polycystic kidney disease) is one of the most frequent genetic diseases in humans. It is characterized by the progressive development of multiple renal cysts affecting all segments of the nephron. Other manifestations include the formation of cysts in the liver and pancreas as well as intracranial aneurysms and cardiovascular defects. ADPKD (autosomal dominant polycystic kidney disease) typically leads to renal insufficiency with progression to end-stage renal disease by late middle age.
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Approximately 85% of ADPKD (autosomal dominant polycystic kidney disease) cases are associated with mutations in the PKD1 (polycystic kidney disease 1) gene. This PKD1 (polycystic kidney disease 1) gene is large, spans 54 kb, and consists of 46exons. It generates a 14.2-kb transcript and encodes a 4,302-amino-acid protein called polycystin-1(4, 9-11). Human PKD1 (polycystic kidney disease 1) and polycystin-1 expression have been analyzed in normal and ADPKD (autosomal dominant polycystic kidney disease) kidneys. During renal development, polycystin-1 is readily detected in glomerular and tubular epithelial cells(reviewed in reference 37 and references therein). In normal adults, we and others have shown that PKD1 (polycystic kidney disease 1) RNA and protein are expressed at moderate to low levels in the collecting and distal tubules, whereas levels increased (~2-fold) in ADPKD (autosomal dominant polycystic kidney disease) kidneys(22, 39). Interestingly, persistent or enhanced polycystin-1 expression is detected in the majority of renal epithelial cysts, although staining was absent in a significant minority of cysts (29).In addition to the kidneys, PKD1 (polycystic kidney disease 1) expression is normally widespread in other adult tissues, including epithelial and nonepithelial cell types (6,14,18,29,30,39).
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More than 200 different PKD1 (polycystic kidney disease 1) mutations have been described, most of which are deletion-insertion, frameshift, or nonsense mutations. These are predicted to result in truncated forms of the protein, consistent with the inactivation of one allele. However, significant proportions are missense or in-frame mutations that are found throughout the gene and are often unique to a particular family(33, 34). As the name implies, ADPKD (autosomal dominant polycystic kidney disease) is dominant and the transmitted mutated PKD1 (polycystic kidney disease 1) allele is sufficient to produce the disease. However, the focal nature of the renal cysts in ADPKD (autosomal dominant polycystic kidney disease) suggests that the mutational mechanism for PKD1 (polycystic kidney disease 1) could be a two-hit or a loss of heterozygosity. Support for this mechanism was obtained by the detection of PKD1 (polycystic kidney disease 1) clonal somatic mutations in cells from a significant proportion of cysts(3,21, 32). A mechanism of loss of heterozygosity could account for the widely varying phenotype commonly observed in individual families.
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Studies on the mouse PKD1 (polycystic kidney disease 1) gene may provide valuable insights into PKD1 (polycystic kidney disease 1) function(s) because of the close similarity between the human and murine gene and gene product. In normal development, murine PKD1 (polycystic kidney disease 1) is expressed at high levels from the morula stage and is detected in all neural crest cell derivatives, including the adult brain, aortic arch, cartilage, and mesenchymal condensation (16,17). Homozygous mutant mice targeted for PKD1 (polycystic kidney disease 1) deletion have been reported to die in utero and to develop renal and pancreatic cysts (2, 19, 24-26, 40). These previous attempts to generate mouse models unfortunately did not provide viable animals postnatally. Nevertheless, the occurrence of renal cysts in this homozygous PKD1 (polycystic kidney disease 1) mutant mice would be consistent with the hypothesis of a two-hit mutational mechanism in humans that involves a germline mutation and somatic inactivation of the normal allele. However, mice heterozygous for the PKD1 (polycystic kidney disease 1) targeted deletion also displayed PKD with occasional liver and pancreatic cysts despite a late adult-onset, supporting a mechanism of haploinsufficiency or gene dosage reduction. Moreover, loss of heterozygosity or haploinsufficiency may not be the sole mechanism for ADPKD (autosomal dominant polycystic kidney disease) pathogenesis. Indeed, these mechanisms are at variance with the persistent or enhanced expression of PKD1 (polycystic kidney disease 1) seen in the majority of human renal cysts unless nonfunctional proteins are produced. This finding of sustained or increased PKD1 (polycystic kidney disease 1) expression raises the question of whether a gain of function or overexpression may be operant.
FIG.1. Schematic representation and detailed restriction map analysis of a murine PKD1 (polycystic kidney disease 1)-BAC.Genomic DNA digestion patterns of the PKD1 (polycystic kidney disease 1)-BAC was compared to that of the PKD1 (polycystic kidney disease 1) locus in the 129Sv and C57Bl/6J inbred mouse strains. Seven probes encompassing most of the murine PKD1 (polycystic kidney disease 1) gene were produced:(a)exon1,(b)exon2-3,(c)exon 7-15, (d) exon 15-20,(e) exon25-34,(f)exon36-45,and(g)exon 45-46,labeled a to g on the genomic PKD1 (polycystic kidney disease 1) representation and over individual blots. Southern blot analysis following restriction digests (BamHI, EcoRI, HindIII, and KpnI） of genomic DNA from the PKD1 (polycystic kidney disease 1)-BAC and murine PKD1 (polycystic kidney disease 1) loci showed identical patterns with all seven probes. M，λ HindlII marker;129，129/Sv; C57, C57Bl/6J.
To investigate the PKD1 (polycystic kidney disease 1) gain-of-function pathogenetic mechanism, we have isolated and characterized a murine PKD1 (polycystic kidney disease 1) bacterial artificial chromosome PKD1 (polycystic kidney disease 1)-BAC) that was subsequently modified by homologous recombination in Escherichia coli to target expression of PKD1 (polycystic kidney disease 1) specifically to the kidneys. We report the production of three transgenic lines that expressed the PKD1 (polycystic kidney disease 1) transgene at different levels. All mice reproducibly displayed a number of similarities to human ADPKD (autosomal dominant polycystic kidney disease) and consistently developed early-onset with rapid progression of renal morphological and functional alterations and died of renal failure by middle age. In addition, the current study describes an in vivo mechanism by which PKD1 (polycystic kidney disease 1) can mediate this PKD phenotype. These mice represent the first model of PKD (polycystic kidney disease) produced by the sole renal overexpression of the orthologous PKD1 (polycystic kidney disease 1) gene.
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