Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases

Gall, Emilie Cornec-Le; Torres, Vicente E.; Harris, Peter C.

doi:10.1681/asn.2017050483

Cited by 262 publications

(198 citation statements)

References 105 publications

(151 reference statements)

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“…More rarely, PLD can occur in isolation from ADPKD, due to mutations in other genes such as protein kinase C substrate 80 K-H ( PRKCSH ), SEC63 , SEC61B , alpha-1,3-glucosyltransferase ( ALG8 ) and low-density lipoprotein receptor-related protein 5 ( LRP5 ), leading to autosomal dominant polycystic liver disease (ADPLD) 7–10. There is however increasing recognition of a phenotypic overlap between patients with ADPKD and ADPLD with a spectrum of disease severity 11 12…”

Section: Introductionmentioning

confidence: 99%

Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis

2020

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ObjectivesA number of randomised control trials (RCTs) investigating the effects of long-acting somatostatin analogues in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD) have been recently reported. We sought to evaluate all available RCTs investigating the efficacy of somatostatin analogues treatment in ADPKD and PLD.Data sourcesElectronic databases; Pubmed, Clincaltrials.gov and Cochrane Central Register of Controlled TrialsEligibility criteria for selecting studiesRCTs and randomised cross-over trials comparing the effects of somatostatin analogue treatment with controls in patients with ADPKD or PLD.Data extraction and synthesisData extraction and bias assessments were performed by two independent reviewers between January and May 2019. Outcomes assessed included estimated glomerular filtration rate (eGFR), total kidney volume (TKV), total liver volume (TLV), progression to end stage renal failure (ESRF) and adverse effects. Data were pooled using a random-effects model and reported as relative risk or mean difference with 95% CIs.ResultsMeta-analysis was performed of six RCTs or randomised cross-over trials and three secondary analyses. A total of 592 patients were included. Compared with controls, somatostatin analogue treatment significantly reduced TLV (mean difference −0.15 L, 95% CI −0.26 to −0.03, p=0.01). There was no significant effect on TKV (mean difference −0.19 L, 95% CI −0.50 to 0.12, p=0.23) or eGFR (mean difference 0.27 mL/min/1.73 m2, 95% CI −2.03 to 2.57, p=0.82). There was no effect on progression to ESRF. Somatostatin analogues were associated with known adverse effects such as gastrointestinal symptoms.ConclusionsThe available RCT data show improvement in TLV with somatostatin analogue treatment. There was no benefit to TKV or eGFR in patients with ADPKD, while being associated with various side effects. Further studies are needed to assess potential benefit in reducing cyst burden in patients with PLD.

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Section: Introductionmentioning

confidence: 99%

Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis

2020

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“…The typical renal phenotype of ADPKD is the insidious development of hundreds of renal cysts. Cysts begin forming during early stages of development and grow progressively throughout the life of the individual (4,5). About half of those affected with ADPKD will progress to end-stage renal failure necessitating dialysis or kidney transplantation (6).…”

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confidence: 99%

Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling

Aboudehen¹,

Farahani²,

Kanchwala

et al. 2018

Journal of Biological Chemistry

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Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, and Long noncoding RNAs (lncRNA), defined by a length >200 nucleotides and absence of a long ORF, have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA-Seq to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific and mutant mice). We identified a kidney-specific, evolutionarily conserved lncRNA called that was down-regulated in cystic kidneys from and mutant mice. The human ortholog was down-regulated in cystic kidneys from ADPKD patients. was highly expressed in renal tubules in adult WT mice, whereas its expression was lost in the cyst epithelium of mutant mice. To investigate the function of, we utilized CRISPR/Cas9 to knock out its expression in mIMCD3 cells. Deletion of resulted in increased phosphorylation of mTOR and its downstream targets, including p70 S6 kinase, ribosomal protein S6, and the translation repressor 4E-BP1. Consistent with activation of mTORC1 signaling, mutant cells displayed increased mitochondrial respiration. The mutant phenotype was partially rescued upon re-expression of in knockout cells. These findings identify as a novel lncRNA that is down-regulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.

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“…ADPKD is the most common life-threatening hereditary renal disease, with an incidence of 1 : 400 to 1 : 1000 individuals [ 88 ]. Disease severity is highly variable, displaying distinct phenotypes ranging from manifestations in utero or during infancy (very early onset (VEO) disease) to clinically silent disease well into the second or third decade of life [ 89 , 90 ]. In contrast, ARPKD typically presents much earlier (1 : 20000 live births among Caucasians).…”

Section: Mtor Inhibition and Renal Diseasesmentioning

confidence: 99%

Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges

Viana

Reis

Alves

2018

Oxidative Medicine and Cellular Longevity

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The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has a key role in the regulation of a variety of biological processes pivotal for cellular life, aging, and death. Impaired activity of mTOR complexes (mTORC1/mTORC2), particularly mTORC1 overactivation, has been implicated in a plethora of age-related disorders, including human renal diseases. Since the discovery of rapamycin (or sirolimus), more than four decades ago, advances in our understanding of how mTOR participates in renal physiological and pathological mechanisms have grown exponentially, due to both preclinical studies in animal models with genetic modification of some mTOR components as well as due to evidence coming from the clinical experience. The main clinical indication of rapamycin is as immunosuppressive therapy for the prevention of allograft rejection, namely, in renal transplantation. However, considering the central participation of mTOR in the pathogenesis of other renal disorders, the use of rapamycin and its analogs meanwhile developed (rapalogues) everolimus and temsirolimus has been viewed as a promising pharmacological strategy. This article critically reviews the use of mTOR inhibitors in renal diseases. Firstly, we briefly overview the mTOR components and signaling as well as the pharmacological armamentarium targeting the mTOR pathway currently available or in the research and development stages. Thereafter, we revisit the mTOR pathway in renal physiology to conclude with the advances, drawbacks, and challenges regarding the use of mTOR inhibitors, in a translational perspective, in four classes of renal diseases: kidney transplantation, polycystic kidney diseases, renal carcinomas, and diabetic nephropathy.

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Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases

Cited by 262 publications

References 105 publications

Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis

Long-acting somatostatin analogue treatments in autosomal dominant polycystic kidney disease and polycystic liver disease: a systematic review and meta-analysis

Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling

Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges

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