scholarly journals mtor Haploinsufficiency Ameliorates Renal Cyst Formation in Adult Zebrafish tmem67 Mutants

2019 ◽  
Author(s):  
Ping Zhu ◽  
Qi Qiu ◽  
Peter C. Harris ◽  
Xiaolei Xu ◽  
Xueying Lin
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Therapeutic Strategy ◽  
Cyst Formation ◽  
Zebrafish Embryos ◽  
Adult Fish ◽  
Adult Zebrafish ◽  
Polycystic Kidney ◽  
Mtor Inhibition ◽  
Fish Model

AbstractAlthough zebrafish embryos have been utilized to study ciliogenesis and to model polycystic kidney disease (PKD), adult zebrafish remain unexplored. Here, we report the generation and characterization of a zebrafish mutant of tmem67, a homologue of the mammalian causative gene for Meckel syndrome type 3 (MKS3). Although a small population of homozygous embryos exhibited pronephric cysts, all mutants were able to survive to adulthood and developed progressive mesonephric cysts with full penetrance. The cysts in the adult zebrafish kidneys manifested features of mammalian PKD, including switching of cyst origin from the proximal tubules to the collecting ducts, increased proliferation of cyst-lining epithelial cells, and hyperactive mTOR signaling. Consistent ciliary abnormalities were observed in both the embryonic and adult zebrafish mutants compared with the wild-type fish, including shorter and fewer single cilia in the distal pronephros and all segments of the mesonephros and greater numbers of multiciliated cells (MCCs). Lack of single cilium preceded cystogenesis, suggestive of a primary defect. Expansion of MCCs occurred after pronephric cyst formation and was inversely correlated with the severity of cystogenesis in young adult zebrafish, suggesting an adaptive action. Interestingly, mTOR inhibition ameliorated renal cysts in both the embryonic and adult zebrafish models; however, it only rescued ciliary abnormalities in the adult mutants. In summary, we have established a tmem67 mutant as the first adult zebrafish PKD model, revealed a novel aspect of cilium regulation, and identified sustained mTOR inhibition as a candidate therapeutic strategy for tmem67-based PKD.Significance StatementWhile zebrafish embryos are well recognized for their value in studying ciliogenesis and polycystic kidney disease (PKD), adult zebrafish have not commonly been used. Here, we report the establishment of the first adult zebrafish model for PKD, which exhibits characteristics of mammalian PKD and shows kidney ciliary abnormalities consistent with those observed in an embryonic model. We also provide evidence for mTOR inhibition as a therapeutic strategy for this particular type of cystogenesis. Compared to the embryonic model, the adult fish model exhibits a spectrum of progressive pathogeneses and enables ciliary abnormalities to be discerned as either primary or secondary to cystogenesis. We believe that this novel adult fish model will facilitate mechanistic studies and therapeutic development for PKD.

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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