The Molecular Basis of Focal Cyst Formation in Human Autosomal Dominant Polycystic Kidney Disease Type I

BackgroundPKD1 or PKD2, the two main causal genes for autosomal dominant polycystic kidney disease (ADPKD), encode the multipass transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Polycystins localize to the primary cilium, an organelle essential for cell signaling, including signal transduction of the Hedgehog pathway. Mutations in ciliary genes that build and maintain the cilium also cause renal cystic disease through unknown pathways. Although recent studies have found alterations in Hedgehog signaling in ADPKD-related models and tissues, the relationship between Hedgehog and polycystic kidney disease is not known.MethodsTo examine the potential role of cell-autonomous Hedgehog signaling in regulating kidney cyst formation in vivo in both early- and adult-onset mouse models of ADPKD, we used conditional inactivation of Pkd1 combined with conditional modulation of Hedgehog signaling components in renal epithelial cells, where mutations in Pkd1 initiate cyst formation. After increasing or decreasing levels of Hedgehog signaling in cells that underwent inactivation of Pkd1, we evaluated the effects of these genetic manipulations on quantitative parameters of polycystic kidney disease severity.ResultsWe found that in Pkd1 conditional mutant mouse kidneys, neither downregulation nor activation of the Hedgehog pathway in epithelial cells along the nephron significantly influenced the severity of the polycystic kidney phenotype in mouse models of developmental or adult-onset of ADPKD.ConclusionsThese data suggest that loss of Pkd1 function results in kidney cysts through pathways that are not affected by the activity of the Hedgehog pathway.

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Somatostatin in renal physiology and autosomal dominant polycystic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz054 ◽

2019 ◽

Vol 35 (8) ◽

pp. 1306-1316 ◽

Cited By ~ 1

Author(s):

A Lianne Messchendorp ◽

Niek F Casteleijn ◽

Esther Meijer ◽

Ron T Gansevoort

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Unmet Need ◽

Cyst Formation ◽

Renal Physiology ◽

Intracellular Camp ◽

Kidney Volume ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3′,5′-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD.

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Pkd1-targeted mutation reveals a role for the Wolffian duct in autosomal dominant polycystic kidney disease

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174419000436 ◽

2019 ◽

Vol 11 (1) ◽

pp. 78-85 ◽

Cited By ~ 1

Author(s):

J. B. Tee ◽

A. V. Dnyanmote ◽

M. K. Lorenzo ◽

O. R. Lee ◽

S. Grisaru ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

High Throughput Sequencing ◽

Autosomal Dominant ◽

Cyst Formation ◽

Wolffian Duct ◽

Renal Tubules ◽

Polycystic Kidney ◽

Cystic Kidneys ◽

Autosomal Dominant Polycystic Kidney

AbstractSeveral life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

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Rhombencephalosynapsis associated with autosomal dominant polycystic kidney disease Type 1

Journal of Neurosurgery Pediatrics ◽

10.3171/ped.2008.2.12.435 ◽

2008 ◽

Vol 2 (6) ◽

pp. 435-437 ◽

Cited By ~ 5

Author(s):

Robert Elliott ◽

David H. Harter

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Chromosomal Abnormalities ◽

Disease Type ◽

Clear Pattern ◽

Polycystic Kidney ◽

Cerebellar Peduncles ◽

Autosomal Dominant Polycystic Kidney

Rhombencephalosynapsis (RES) is a rare congenital malformation of the cerebellum characterized by hypogenesis or agenesis of the vermis and fusion of the cerebellar hemispheres with or without fusion of the dentate nuclei and superior cerebellar peduncles. No genetic or chromosomal abnormalities have been identified for RES. Although the occurrence of RES is presumed to be sporadic, no clear pattern of inheritance has been identified. The authors report on a 17-year-old girl with autosomal dominant polycystic kidney disease Type 1 as well as RES.

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A role for CFTR in human autosomal dominant polycystic kidney disease

AJP Cell Physiology ◽

10.1152/ajpcell.1996.270.1.c389 ◽

1996 ◽

Vol 270 (1) ◽

pp. C389-C399 ◽

Cited By ~ 94

Author(s):

K. Hanaoka ◽

O. Devuyst ◽

E. M. Schwiebert ◽

P. D. Wilson ◽

W. B. Guggino

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Primary Cultures ◽

Cyst Formation ◽

Disulfonic Acid ◽

Polycystic Kidney ◽

Acid Sensitivity ◽

Autosomal Dominant Polycystic Kidney

Human autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal dominant hereditary disorder characterized by enormous renal enlargement and the development of multiple cysts originating from nephrons. We investigated the pathogenesis of cyst formation in ADPKD by using patch-clamp and immunocytochemical techniques. Adenosine 3',5'-cyclic monophosphate-activated Cl- currents are present in primary cultures of ADPKD cells and have characteristics such as a linear current-voltage relation, insensitivity to 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, sensitivity to glibenclamide and diphenylamine carboxylic acid, and an anion selectivity sequence of Br- > Cl- > I- > glutamate, all of which are identical to cystic fibrosis transmembrane conductance regulator (CFTR). With the use of CFTR antibodies raised against the regulatory and first nucleotide-binding domains, CFTR was detected in primary cultures of ADPKD cells. Similar results were obtained in vivo in cyst-lining epithelial cells in ADPKD kidneys, where staining was seen associated with the apical membrane regions. These data indicate that the CFTR Cl- channel exists in apical membranes of ADPKD cells and may play an important role in cyst formation or enlargement.

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On new hypotheses about autosomal dominant polycystic kidney disease type 1

Medical Hypotheses ◽

10.1054/mehy.2001.1482 ◽

2001 ◽

Vol 57 (6) ◽

pp. 754-758 ◽

Cited By ~ 1

Author(s):

E. Bersani ◽

V. De Fonzo ◽

F. Aluffi-Pentini ◽

V. Parisi

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Disease Type ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney

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Monkeys mutant for PKD1 recapitulate human autosomal dominant polycystic kidney disease

Nature Communications ◽

10.1038/s41467-019-13398-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 4

Author(s):

Tomoyuki Tsukiyama ◽

Kenichi Kobayashi ◽

Masataka Nakaya ◽

Chizuru Iwatani ◽

Yasunari Seita ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Disease Onset ◽

Cyst Formation ◽

Polycystic Kidney ◽

Hereditary Disorders ◽

Allele Specific ◽

Drug Treatments ◽

Autosomal Dominant Polycystic Kidney

AbstractAutosomal dominant polycystic kidney disease (ADPKD) caused by PKD1 mutations is one of the most common hereditary disorders. However, the key pathological processes underlying cyst development and exacerbation in pre-symptomatic stages remain unknown, because rodent models do not recapitulate critical disease phenotypes, including disease onset in heterozygotes. Here, using CRISPR/Cas9, we generate ADPKD models with PKD1 mutations in cynomolgus monkeys. As in humans and mice, near-complete PKD1 depletion induces severe cyst formation mainly in collecting ducts. Importantly, unlike in mice, PKD1 heterozygote monkeys exhibit cyst formation perinatally in distal tubules, possibly reflecting the initial pathology in humans. Many monkeys in these models survive after cyst formation, and cysts progress with age. Furthermore, we succeed in generating selective heterozygous mutations using allele-specific targeting. We propose that our models elucidate the onset and progression of ADPKD, which will serve as a critical basis for establishing new therapeutic strategies, including drug treatments.

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