Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

Cordido, Adrián; Vizoso-Gonzalez, Marta; García-González, Miguel A.

doi:10.3390/ijms22126523

Cited by 23 publications

(48 citation statements)

References 177 publications

(263 reference statements)

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“…ARPKD is a monogenic disease caused mainly by mutations in PKHD1 gene which encodes polyductin (also known as fibrocystin) [26,27]. However, it can also be caused, in a minority percentage, by mutations in DZIP1L gene [28].…”

Section: Autosomal Recessive Polycystic Kidney Disease (Arpkd)mentioning

confidence: 99%

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Gómez-García

Martínez-Pulleiro

Carrera

et al. 2022

Cells

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Genetic kidney diseases (GKDs) are a group of rare diseases, affecting approximately about 60 to 80 per 100,000 individuals, for which there is currently no treatment that can cure them (in many cases). GKDs usually leads to early-onset chronic kidney disease, which results in patients having to undergo dialysis or kidney transplant. Here, we briefly describe genetic causes and phenotypic effects of six GKDs representative of different ranges of prevalence and renal involvement (ciliopathy, glomerulopathy, and tubulopathy). One of the shared characteristics of GKDs is that most of them are monogenic. This characteristic makes it possible to use site-specific nuclease systems to edit the genes that cause GKDs and generate in vitro and in vivo models that reflect the genetic abnormalities of GKDs. We describe and compare these site-specific nuclease systems (zinc finger nucleases (ZFNs), transcription activator-like effect nucleases (TALENs) and regularly clustered short palindromic repeat-associated protein (CRISPR-Cas9)) and review how these systems have allowed the generation of cellular and animal GKDs models and how they have contributed to shed light on many still unknown fields in GKDs. We also indicate the main obstacles limiting the application of these systems in a more efficient way. The information provided here will be useful to gain an accurate understanding of the technological advances in the field of genome editing for GKDs, as well as to serve as a guide for the selection of both the genome editing tool and the gene delivery method most suitable for the successful development of GKDs models.

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Section: Autosomal Recessive Polycystic Kidney Disease (Arpkd)mentioning

confidence: 99%

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Gómez-García

Martínez-Pulleiro

Carrera

et al. 2022

Cells

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“… 1 PCLD is an extrarenal manifestation of autosomal dominant or recessive polycystic kidney disease. 2 , 3 Multiple mechanisms are involved in the development of hepatic cysts. Pathophysiological features include decreased intracellular calcium and subsequent increased intracellular cyclic adenosine monophosphate (cAMP) levels, promoting cholangiocyte proliferation and fluid secretion, and these characteristics are potential targets for pharmacological therapy.…”

Section: Introductionmentioning

confidence: 99%

Evidence of nonsurgical treatment for polycystic liver disease

Yoo

Jung

et al. 2022

Therapeutic Advances in Chronic Disease

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Background: Polycystic liver disease (PCLD) is the most common extrarenal manifestation of polycystic kidney disease. There is an urgent need to assess the efficacy and safety of nonsurgical modalities to relieve symptoms and decrease the severity of PCLD. Herein, we aimed to evaluate the efficacy of the nonsurgical treatment of PCLD and the quality of life of affected patients. Methods: PubMed, Ovid, MEDLINE, EMBASE, and the Cochrane Library were searched for studies on the nonsurgical modalities, either medications or radiological intervention to manage PCLD. Treatment efficacy, adverse events (AEs), and patient quality of life were evaluated. Results: In total, 27 studies involving 1037 patients were selected. After nonsurgical treatment, liver volume decreased by 259 ml/m [mean change (Δ) of 6.22%] and the effect was higher in the radiological intervention group [−1617 ml/m (−15.49%)] than in the medication group [−151 ml/m (−3.78%)]. The AEs and serious AEs rates after overall nonsurgical treatment were 0.50 [95% confidence interval (CI): 0.33–0.67] and 0.04 (95% CI: 0.01–0.07), respectively. The results of the SF-36 questionnaire showed that PCLD treatment improved physical function [physical component summary score of 4.18 (95% CI: 1.54–6.83)] but did not significantly improve mental function [mental component summary score of 0.91 (95% CI: −1.20 to 3.03)]. Conclusion: Nonsurgical treatment was effective and safe for PCLD, but did not improve the quality of life in terms of mental health. Radiological intervention directly reduces hepatic cysts, and thus they should be considered for immediate symptom relief in patients with severe symptoms, whereas medication might be considered for maintenance treatment. Registration number: PROSPERO (International Prospective Register of Systematic Reviews) CRD42021279597

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“…In autosomal dominant polycystic kidney disease (ADPKD), ~85% of the patients develop liver cysts throughout hepatic parenchyma and its severity can range from a few cysts to a severe hepatic cystogenesis [ 3 , 4 ]. Meanwhile, in autosomal recessive polycystic kidney disease (ARPKD), liver cysts could develop, but the principal hepatic complication is a defective remodeling of the ductal plate with congenital hepatic fibrosis [ 5 , 6 ]. For both, PLD is the principal extrarenal manifestation and requires clinical management and treatment [ 2 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

et al. 2022

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(1) Background: Polycystic liver disease (PLD) is a heterogeneous group of congenital disorders characterized by bile duct dilatation and cyst development derived from cholangiocytes. Nevertheless, the cystogenesis mechanism is currently unknown and the PLD treatment is limited to liver transplantation. Novel and efficient therapeutic approaches are th6us needed. In this context, the present work has a principal aim to find novel molecular pathways, as well as new therapeutic targets, involved in the hepatic cystogenesis process. (2) Methods: Quantitative proteomics based on SWATH–MS technology were performed comparing hepatic proteomes of Wild Type and mutant/polycystic livers in a polycystic kidney disease (PKD) murine model (Pkd1cond/cond;Tam-Cre−/+). (3) Results: We identified several proteins altered in abundance, with two-fold cut-off up-regulation or down-regulation and an adjusted p-value significantly related to hepatic cystogenesis. Then, we performed enrichment and a protein–protein analysis identifying a cluster focused on hepatic fibrinogens. Finally, we validated a selection of targets by RT-qPCR, Western blotting and immunohistochemistry, finding a high correlation with quantitative proteomics data and validating the fibrinogen complex. (4) Conclusions: This work identified a novel molecular pathway in cystic liver disease, highlighting the fibrinogen complex as a possible new therapeutic target for PLD.

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Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

Cited by 23 publications

References 177 publications

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

Evidence of nonsurgical treatment for polycystic liver disease

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

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