Pathophysiology of Renal Tubular Cyst Formation in Murine Models of Polycystic Kidney Disease1

2015 ◽  
pp. 23-34 ◽  
Author(s):  
William E. Sweeney ◽  
Ellis D. Avner
Keyword(s):  
Cyst Formation ◽  
Murine Models ◽  
Polycystic Kidney ◽  
Renal Tubular

scholarly journals The cellular pathways and potential therapeutics of Polycystic Kidney Disease

2021 ◽  
Author(s):  
Taylor Richards ◽  
Kavindiya Modarage ◽  
Soniya A. Malik ◽  
Paraskevi Goggolidou
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cellular Proliferation ◽  
Cyst Formation ◽  
Great Promise ◽  
Polycystic Kidney ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Stage Renal Disease

Polycystic Kidney Disease (PKD) refers to a group of disorders, driven by the formation of cysts in renal tubular cells and is currently one of the leading causes of end-stage renal disease. The range of symptoms observed in PKD is due to mutations in cilia-localising genes, resulting in changes in cellular signalling. As such, compounds that are currently in preclinical and clinical trials target some of these signalling pathways that are dysregulated in PKD. In this review, we highlight these pathways including cAMP, EGF and AMPK signalling and drugs that target them and may show promise in lessening the disease burden of PKD patients. At present, tolvaptan is the only approved therapy for ADPKD, however, it carries several adverse side effects whilst comparatively, no pharmacological drug is approved for ARPKD treatment. Aside from this, drugs that have been the subject of multiple clinical trials such as metformin, which targets AMPK signalling and somatostatins, which target cAMP signalling have shown great promise in reducing cyst formation and cellular proliferation. This review also discusses other potential and novel targets that can be used for future interventions, such as β-catenin and TAZ, where research has shown that a reduction in the overexpression of these signalling components results in amelioration of disease phenotype. Thus, it becomes apparent that well-designed preclinical investigations and future clinical trials into these pathways and other potential signalling targets are crucial in bettering disease prognosis for PKD patients and could lead to personalised therapy approaches.

scholarly journals Murine models of polycystic kidney disease

1996 ◽  
Vol 11 (supp6) ◽  
pp. 38-45 ◽  
Author(s):  
G. Schieren ◽  
R. Pey ◽  
J. Bach ◽  
M. Hafner ◽  
N. Gretz
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Murine Models ◽  
Polycystic Kidney

scholarly journals Identifying cystogenic paracrine signaling molecules in cyst fluid of patients with polycystic kidney disease

2019 ◽  
Vol 316 (1) ◽  
pp. F204-F213 ◽  
Author(s):  
Annegien T. Kenter ◽  
Sari E. van Rossum-Fikkert ◽  
Mahdi Salih ◽  
Paul C. M. S. Verhagen ◽  
Geert J. L. H. van Leenders ◽  
...  
Keyword(s):  
Cyst Formation ◽  
Liver Cyst ◽  
Signaling Molecules ◽  
Cyst Fluid ◽  
Size Exclusion ◽  
Signaling Proteins ◽  
Paracrine Signaling ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells ◽  
Exclusion Chromatography

In autosomal dominant polycystic kidney disease (ADPKD) paracrine signaling molecules in cyst fluid can induce proliferation and cystogenesis of neighboring renal epithelial cells. However, the identity of this cyst-inducing factor is still unknown. The aim of this study was to identify paracrine signaling proteins in cyst fluid using a 3D in vitro cystogenesis assay. We collected cyst fluid from 15 ADPKD patients who underwent kidney or liver resection (55 cysts from 13 nephrectomies, 5 cysts from 2 liver resections). For each sample, the ability to induce proliferation and cyst formation was tested using the cystogenesis assay (RPTEC/TERT1 cells in Matrigel with cyst fluid added for 14 days). Kidney cyst fluid induced proliferation and cyst growth of renal epithelial cells in a dose-dependent fashion. Liver cyst fluid also induced cystogenesis. Using size exclusion chromatography, 56 cyst fluid fractions were obtained of which only the fractions between 30 and 100 kDa showed cystogenic potential. Mass spectrometry analysis of samples that tested positive or negative in the assay identified 43 candidate cystogenic proteins. Gene ontology analysis showed an enrichment for proteins classified as enzymes, immunity proteins, receptors, and signaling proteins. A number of these proteins have previously been implicated in ADPKD, including secreted frizzled-related protein 4, S100A8, osteopontin, and cysteine rich with EGF-like domains 1. In conclusion, both kidney and liver cyst fluids contain paracrine signaling molecules that drive cyst formation. Using size exclusion chromatography and mass spectrometry, we procured a candidate list for future studies. Ultimately, cystogenic paracrine signaling molecules may be targeted to abrogate cystogenesis in ADPKD.

scholarly journals Cell-Autonomous Hedgehog Signaling Is Not Required for Cyst Formation in Autosomal Dominant Polycystic Kidney Disease

2019 ◽  
Vol 30 (11) ◽  
pp. 2103-2111 ◽  
Author(s):  
Ming Ma ◽  
Emilie Legué ◽  
Xin Tian ◽  
Stefan Somlo ◽  
Karel F. Liem
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mouse Models ◽  
Hedgehog Signaling ◽  
Autosomal Dominant ◽  
Cyst Formation ◽  
Hedgehog Pathway ◽  
Adult Onset ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

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.

scholarly journals Somatostatin in renal physiology and autosomal dominant polycystic kidney disease

2019 ◽  
Vol 35 (8) ◽  
pp. 1306-1316 ◽  
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.

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

2019 ◽  
Vol 11 (1) ◽  
pp. 78-85 ◽  
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.

scholarly journals Renal tubule Na,K-ATPase polarity in different animal models of polycystic kidney disease.

1995 ◽  
Vol 43 (8) ◽  
pp. 785-790 ◽  
Author(s):  
M R Ogborn ◽  
S Sareen ◽  
K Tomobe ◽  
H Takahashi ◽  
J F Crocker
Keyword(s):  
Kidney Disease ◽  
Animal Models ◽  
Polycystic Kidney Disease ◽  
Renal Tubule ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Epithelial Phenotype ◽  
Electrolyte Flux ◽  
Cyst Development

Apical mislocation of the ubiquitous transport enzyme Na,K-ATPase has been implicated as a feature of cyst development in in vitro studies of human polycystic kidney disease (PKD) epithelia. We undertook an immunohistochemical study of murine glucocorticoid-induced PKD, the pcy mouse, the cpk mouse, and the diphenylthiazole (DPT)-induced rat models of PKD to determine if this feature was common to these models of cyst development. Distribution of Na,K-ATPase was determined with a polyclonal anti-Na,K-ATPase antibody and a nickel-silver-enhanced peroxidase color development system. Results were documented objectively with densitometric techniques. Control animals appropriate to the age, strain, and species of the experimental groups demonstrated the expected polar distribution of Na,K-ATPase to the basolateral surface. This distribution was more marked in mature animals. Tubular dilatation and cystic change, however, were associated with increased apical Na,K-ATPase in all models. The murine models demonstrated decreased basolateral staining for Na,K-ATPase compared with controls, although this was not a feature of the DPT rat model. Abnormal location of Na,K-ATPase is a shared feature of a variety of animal models and human PKD. This may contribute to abnormal fluid and electrolyte flux favoring cyst formation or may represent expression of a less differentiated renal tubule epithelial phenotype.

SaO001THE EFFECT OF L-TYPE AMINO ACID TRANSPORTER 1 IN THE CYST FORMATION OF MODEL MICE FOR POLYCYSTIC KIDNEY DISEASE

2019 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Sayo Takeda ◽  
Saori Nishio ◽  
Toru Kimura ◽  
Junya Yamamoto ◽  
Daigo Nakazawa ◽  
...  
Keyword(s):  
Amino Acid ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cyst Formation ◽  
Amino Acid Transporter ◽  
Polycystic Kidney ◽  
Acid Transporter

scholarly journals Renal tubule Na,K-ATPase polarity in glucocorticoid-induced polycystic kidney disease.

1993 ◽  
Vol 41 (4) ◽  
pp. 555-558 ◽  
Author(s):  
M R Ogborn ◽  
S Sareen ◽  
P C Grimm
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Fluid Transport ◽  
Cyst Formation ◽  
In Vivo Studies ◽  
High Threshold ◽  
Polycystic Kidney ◽  
C3h Mice

Cyst formation in polycystic kidney disease (PKD) involves proliferation of cyst lining epithelial and changes in trans-epithelial fluid and electrolyte transport. In vitro studies have suggested that mislocation of Na,K-ATPase to the apical tubular surface may be an important component of cyst fluid transport. We undertook in vivo studies of Na,K-ATPase location using the "threshold" murine model of glucocorticoid-induced PKD (GIPKD). Using histological, immunohistochemical, and densitometric techniques, we compared cyst formation and the cellular location of Na,K-ATPase in suckling C3H (low threshold for GIPKD) and DBA (high threshold) mice given an inducing dose of 200 mg/kg methylprednisolone acetate. As expected, C3H mice demonstrated greater cyst formation as measured by proportion of section area occupied by the tubule lumen (26.7% vs 15.5%; p < 0.001). Cyst formation was associated with increased Na,K-ATPase staining and increased apical Na,K-ATPase location. MPA treatment in C3H mice resulted in apical staining that exceeded basolateral staining (35.3% of reference window vs 29.8%; p < 0.001). The relatively GIPKD-resistant DBA mice did not show such change in Na,K-ATPase location. These immunohistochemical studies suggest a role for Na,K-ATPase in renal cyst formation.

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