scholarly journals Role of CFTR in Autosomal Recessive Polycystic Kidney Disease

2001 ◽  
Vol 12 (4) ◽  
pp. 719-725
Author(s):  
KOICHI NAKANISHI ◽  
WILLIAM E. SWEENEY ◽  
KATHERINE MACRAE DELL ◽  
CALVIN U. COTTON ◽  
ELLIS D. AVNER
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Murine Model ◽  
Autosomal Recessive ◽  
Renal Cyst ◽  
Fluid Secretion ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Cftr Protein

Abstract. An extensive body of in vitro data implicates epithelial chloride secretion, mediated through cystic fibrosis transmembrane conductance regulator (CFTR) protein, in generating or maintaining fluid filled cysts in MDCK cells and in human autosomal dominant polycystic kidney disease (ADPKD). In contrast, few studies have addressed the pathophysiology of fluid secretion in cyst formation and enlargement in autosomal recessive polycystic kidney disease (ARPKD). Murine models of targeted disruptions or deletions of specific genes have created opportunities to examine the role of individual gene products in normal development and/or disease pathophysiology. The creation of a murine model of CF, which lacks functional CFTR protein, provides the opportunity to determine whether CFTR activity is required for renal cyst formation in vivo. Therefore, this study sought to determine whether renal cyst formation could be prevented by genetic complementation of the BPK murine model of ARPKD with the CFTR knockout mouse. The results of this study reveal that in animals that are homozygous for the cystic gene (bpk), the lack of functional CFTR protein on the apical surface of cystic epithelium does not provide protection against cyst growth and subsequent decline in renal function. Double mutant mice (bpk -/-; cftr -/-) developed massively enlarged kidneys and died, on average, 7 d earlier than cystic, non-CF mice (bpk -/-; cftr +/±). This suggests fundamental differences in the mechanisms of transtubular fluid secretion in animal models of ARPKD compared with ADPKD.

Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease

1993 ◽  
Vol 7 (2) ◽  
pp. 163-172 ◽  
Author(s):  
Jeroen Nauta ◽  
Yuko Ozawa ◽  
William E. Sweeney ◽  
Joe C. Rutledge ◽  
Ellis D. Avner
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Murine Model ◽  
Autosomal Recessive ◽  
Polycystic Kidney

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

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.

scholarly journals cAMP Regulates Cell Proliferation and Cyst Formation in Autosomal Polycystic Kidney Disease Cells

2000 ◽  
Vol 11 (7) ◽  
pp. 1179-1187 ◽  
Author(s):  
KAZUSHIGE HANAOKA ◽  
WILLIAM B. GUGGINO
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Kidney Disease ◽  
Epidermal Growth Factor ◽  
Fluid Secretion ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Epidermal Growth ◽  
Cyst Growth

Abstract. Both epithelial cell proliferation and fluid accumulation are responsible for cyst growth in autosomal dominant polycystic kidney disease (ADPKD). It was previously reported that the cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in cysts from ADPKD patients and suggested that cAMP-stimulated Cl-and fluid secretion occurs through CFTR. The purpose of this study was to investigate the role of cell proliferation in cyst formation in ADPKD and to explore further the role of fluid secretion in cyst growth. Primary cultures both of ADPKD epithelial cells and a mixed population of normal renal epithelial cells isolated from the cortex (HRCE cells) were used. This study tested whether cAMP was involved both in stimulating cell proliferation and formation of cystsin vitro.3H-Thymidine incorporation assays showed that epidermal growth factor stimulated proliferation both in ADPKD cells and HRCE cells. In addition, cAMP stimulated DNA synthesis and cell proliferation in ADPKD, but not HRCE, cells. The effects of cAMP and epidermal growth factor on cell growth in ADPKD cells were additive. cAMP also stimulated cyst enlargement and fluid secretion in ADPKD cells. By contrast, cyst formation and enlargement from HRCE cells occurred without cAMP. Fluid secretion into the cyst lumen was blocked by diphenylamine carboxylic acid (DPC) and glibenclamide in ADPKD cells but blocked only by DPC in HRCE cells. This study showed that ADPKD cells have unique characteristics ; cAMP stimulates fluid secretion and cell proliferation, indicating cAMP plays a very important role in cyst growth during the course of ADPKD.

scholarly journals Renal endothelin system in polycystic kidney disease.

1998 ◽  
Vol 9 (7) ◽  
pp. 1169-1177 ◽  
Author(s):  
B Hocher ◽  
R Zart ◽  
A Schwarz ◽  
V Vogt ◽  
C Braun ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Renal Cyst ◽  
Cyst Formation ◽  
Receptor Subtypes ◽  
Endothelin Receptor ◽  
Polycystic Kidney ◽  
Endothelin System

Polycystic kidney disease (PKD) is characterized by interstitial fibrosis and formation of renal cysts. Interestingly, interstitial fibrosis and renal cyst formation were also seen in human endothelin-1 (ET-1) transgenic mice. This study, therefore, analyzes the tissue distribution of ET-1, the tissue concentrations of ET-1, as well as the expression of ET receptor subtypes in the kidneys of a rat model of PKD: Han:SPRD rats. Six-week-old heterozygous (cy/+) and homozygous (cy/cy), as well as 6-mo-old heterozygous (cy/+) Han:SPRD rats and the corresponding age-matched Sprague Dawley littermates (SD) (+/+) were analyzed. Furthermore, the acute effects of the mixed (A/B) endothelin receptor antagonist bosentan on hemodynamic and renal function were investigated in 6-mo-old, conscious, chronically instrumented (cy/+) rats. The kidneys of affected rats showed significantly elevated tissue levels of ET-1 compared with age-matched controls (3.5 +/- 0.3-fold in young cy/cy rats, P < 0.01; 1.4 +/- 0.2-fold in young cy/+ rats, P < 0.01; 6.2 +/- 0.4-fold in old cy/+ rats, P < 0.001) due to a highly increased ET-1 synthesis within the epithelial cells of the cysts. Analyzing tissue sections from patients with typical autosomal dominant PKD demonstrated a high ET-1 expression within the epithelial cells of the cysts as well. Scatchard analysis revealed a markedly decreased ETA and ETB receptor density in all groups of affected rats. The acute blockade of both endothelin receptor subtypes using bosentan in 6-mo-old heterozygous PKD rats led to a significant decrease in mean arterial BP (MAP) (-19.7 +/- 2.1 mmHg, P < 0.05) and GFR (-41 +/- 5%, P < 0.005). Renal blood flow (RBF) was significantly increased (+2.1 +/- 0.5 ml/min, P < 0.05) after bosentan, whereas bosentan had no effect on MAP, GFR, and RBF in age-matched controls. These data show that the paracrine renal endothelin system is activated in PKD and participates in the regulation of MAP, GFR, RBF, and possibly contributes to renal cyst formation and fibrosis.

scholarly journals Evidence for a “Pathogenic Triumvirate” in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Lu Jiang ◽  
Pingping Fang ◽  
James L. Weemhoff ◽  
Udayan Apte ◽  
Michele T. Pritchard
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Hepatic Fibrosis ◽  
Cyst Wall ◽  
Autosomal Recessive ◽  
Fluid Secretion ◽  
Congenital Hepatic Fibrosis ◽  
Therapeutic Approaches ◽  
Polycystic Kidney ◽  
Cyst Growth

Autosomal recessive polycystic kidney disease (ARPKD) is a severe monogenic disorder that occurs due to mutations in thePKHD1gene. Congenital hepatic fibrosis (CHF) associated with ARPKD is characterized by the presence of hepatic cysts derived from dilated bile ducts and a robust, pericystic fibrosis. Cyst growth, due to cyst wall epithelial cell hyperproliferation and fluid secretion, is thought to be the driving force behind disease progression. Liver fibrosis is a wound healing response in which collagen accumulates in the liver due to an imbalance between extracellular matrix synthesis and degradation. Whereas both hyperproliferation and pericystic fibrosis are hallmarks of CHF/ARPKD, whether or not these two processes influence one another remains unclear. Additionally, recent studies demonstrate that inflammation is a common feature of CHF/ARPKD. Therefore, we propose a “pathogenic triumvirate” consisting of hyperproliferation of cyst wall growth, pericystic fibrosis, and inflammation which drives CHF/ARPKD progression. This review will summarize what is known regarding the mechanisms of cyst growth, fibrosis, and inflammation in CHF/ARPKD. Further, we will discuss the potential advantage of identifying a core pathogenic feature in CHF/ARPKD to aid in the development of novel therapeutic approaches. If a core pathogenic feature does not exist, then developing multimodality therapeutic approaches to target each member of the “pathogenic triumvirate” individually may be a better strategy to manage this debilitating disease.

EP2 receptor mediates PGE2-induced cystogenesis of human renal epithelial cells

2007 ◽  
Vol 293 (5) ◽  
pp. F1622-F1632 ◽  
Author(s):  
Gerard Elberg ◽  
Dorit Elberg ◽  
Teresa V. Lewis ◽  
Suresh Guruswamy ◽  
Lijuan Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Cyst Formation ◽  
Cyst Fluid ◽  
Receptor Expression ◽  
Camp Signaling ◽  
Polycystic Kidney ◽  
Camp Formation

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by formation of cysts from tubular epithelial cells. Previous studies indicate that secretion of prostaglandin E2 (PGE2) into cyst fluid and production of cAMP underlie cyst expansion. However, the mechanism by which PGE2 directly stimulates cAMP formation and modulates cystogenesis is still unclear, because the particular E-prostanoid (EP) receptor mediating the PGE2 effect has not been characterized. Our goal is to define the PGE2 receptor subtype involved in ADPKD. We used a three-dimensional cell-culture system of human epithelial cells from normal and ADPKD kidneys in primary cultures to demonstrate that PGE2 induces cyst formation. Biochemical evidence gathered by using real-time RT-PCR mRNA analysis and immunodetection indicate the presence of EP2 receptor in cystic epithelial cells in ADPKD kidney. Pharmacological evidence obtained by using PGE2-selective analogs further demonstrates that EP2 mediates cAMP formation and cystogenesis. Functional evidence for a role of EP2 receptor in mediating cAMP signaling was also provided by inhibiting EP2 receptor expression with transfection of small interfering RNA in cystic epithelial cells. Our results indicate that PGE2 produced in cyst fluid binds to adjacent EP2 receptors located on the apical side of cysts and stimulates EP2 receptor expression. PGE2 binding to EP2 receptor leads to cAMP signaling and cystogenesis by a mechanism that involves protection of cystic epithelial cells from apoptosis. The role of EP2 receptor in mediating the PGE2 effect on stimulating cyst formation may have direct pharmacological implications for the treatment of polycystic kidney disease.

scholarly journals MP037THE ROLE OF DNA ANALYSIS IN DIAGNOSIS OF AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE

2016 ◽  
Vol 31 (suppl_1) ◽  
pp. i355-i355
Author(s):  
Lena Obeidova ◽  
Veronika Elisakova ◽  
Tomas Seeman ◽  
Jana Reiterova ◽  
Jitka Stekrova
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Dna Analysis ◽  
Polycystic Kidney

scholarly journals Autosomal Recessive Polycystic Kidney Disease—The Clinical Aspects and Diagnostic Challenges

2020 ◽  
Author(s):  
Dorota Wicher ◽  
Łukasz Obrycki ◽  
Irena Jankowska
Keyword(s):  
Genetic Testing ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Multidisciplinary Approach ◽  
Growth Failure ◽  
Clinical Aspects ◽  
Polycystic Kidney ◽  
Clinical Criteria

AbstractAutosomal recessive polycystic kidney disease (ARPKD) is one of the most common ciliopathies with kidney (nephromegaly, hypertension, renal dysfunction) and liver involvement (congenital hepatic fibrosis, dilated bile ducts). Clinical features also include growth failure and neurocognitive impairment. Plurality of clinical aspects requires multidisciplinary approach to treatment and care of patients. Until recently, diagnosis was based on clinical criteria. Results of genetic testing show the molecular basis of polycystic kidneys disease is heterogeneous, and differential diagnosis is essential. The aim of the article is to discuss the role of genetic testing and its difficulties in diagnostics of ARPKD in children.

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