Autosomal Dominant Polycystic Kidney Disease – Genetics and Cyst Formation

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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

Cell ◽

10.1016/s0092-8674(00)81793-6 ◽

1996 ◽

Vol 87 (6) ◽

pp. 979-987 ◽

Cited By ~ 374

Author(s):

Feng Qian ◽

Terry J Watnick ◽

Luiz F Onuchic ◽

Gregory G Germino

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Molecular Basis ◽

Autosomal Dominant ◽

Cyst Formation ◽

Disease Type ◽

Type I ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney

Download Full-text

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.

Download Full-text

Autosomal dominant polycystic kidney disease in absence of renal cyst formation illustrates genetic interaction between WT1 and PKD1

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106633 ◽

2020 ◽

pp. jmedgenet-2019-106633

Author(s):

Johannes Münch ◽

Karin M Kirschner ◽

Hendrik Schlee ◽

Cornelia Kraus ◽

Ria Schönauer ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Genetic Interaction ◽

Renal Cyst ◽

Family Members ◽

Cyst Formation ◽

Polycystic Kidney ◽

Pathogenic Variants ◽

Autosomal Dominant Polycystic Kidney

PurposeAutosomal dominant polycystic kidney disease (ADPKD), caused by pathogenic variants of either PKD1 or PKD2, is characterised by wide interfamilial and intrafamilial phenotypic variability. This study aimed to determine the molecular basis of marked clinical variability in ADPKD family members and sought to analyse whether alterations of WT1 (Wilms tumour 1), encoding a regulator of gene expression, may have an impact on renal cyst formation.MethodsADPKD family members underwent clinical and molecular evaluation. Functionally, Pkd1 mRNA and protein expression upon Wt1 knockdown was evaluated in mouse embryonic kidneys and mesonephric M15 cells.ResultsBy renal gene panel analysis, we identified two pathogenic variants in an individual with maternal history of ADPKD, however, without cystic kidneys but polycystic liver disease: a known PKD1 missense variant (c.8311G>A, p.Glu2771Lys) and a known de novo WT1 splice site variant (c.1432+4C>T). The latter was previously associated with imbalanced +/−KTS isoform ratio of WT1. In ex vivo organ cultures from mouse embryonic kidneys, Wt1 knockdown resulted in decreased Pkd1 expression on mRNA and protein level.ConclusionWhile the role of WT1 in glomerulopathies has been well established, this report by illustrating genetic interaction with PKD1 proposes WT1 as potential modifier in ADPKD.

Download Full-text

Cyst formation and growth in autosomal dominant polycystic kidney disease

Kidney International ◽

10.1038/ki.1987.121 ◽

1987 ◽

Vol 31 (5) ◽

pp. 1145-1152 ◽

Cited By ~ 215

Author(s):

Jared J. Grantham ◽

James L. Geiser ◽

Andrew P. Evan

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Cyst Formation ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney

Download Full-text

Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

Molecular and Cellular Biology ◽

10.1128/mcb.00337-17 ◽

2017 ◽

Vol 37 (24) ◽

Cited By ~ 40

Author(s):

Yu Ishimoto ◽

Reiko Inagi ◽

Daisuke Yoshihara ◽

Masanori Kugita ◽

Shizuko Nagao ◽

...

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Epithelial Cell ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Cyst Formation ◽

Polycystic Kidney ◽

Mitochondrial Dna Copy Number ◽

Model Animal ◽

Autosomal Dominant Polycystic Kidney

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1 flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression were decreased in ADPKD model animal kidneys, with PGC-1α expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1α expression was suppressed by decreased intracellular Ca2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD.

Download Full-text