scholarly journals Cyst Reduction by Melatonin in a Novel Drosophila Model of Polycystic Kidney Disease

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5477
Author(s):  
Cassandra Millet-Boureima ◽  
Roman Rozencwaig ◽  
Felix Polyak ◽  
Chiara Gamberi
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Malpighian Tubules ◽  
Cystic Degeneration ◽  
Renal Tubules ◽  
Potential Candidate ◽  
Polycystic Kidney ◽  
Melatonin Administration ◽  
Drosophila Model ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive cystic degeneration of the renal tubules, the nephrons, eventually severely compromising kidney function. ADPKD is incurable, with half of the patients eventually needing renal replacement. Treatments for ADPKD patients are limited and new effective therapeutics are needed. Melatonin, a central metabolic regulator conserved across all life kingdoms, exhibits oncostatic and oncoprotective activity and no detected toxicity. Here, we used the Bicaudal C (BicC) Drosophila model of polycystic kidney disease to test the cyst-reducing potential of melatonin. Significant cyst reduction was found in the renal (Malpighian) tubules upon melatonin administration and suggest mechanistic sophistication. Similar to vertebrate PKD, the BicC fly PKD model responds to the antiproliferative drugs rapamycin and mimics of the second mitochondria-derived activator of caspases (Smac). Melatonin appears to be a new cyst-reducing molecule with attractive properties as a potential candidate for PKD treatment.

scholarly journals Cyst Reduction in a Polycystic Kidney Disease Drosophila Model Using Smac Mimics

Biomedicines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 82 ◽  
Author(s):  
Cassandra Millet-Boureima ◽  
Ramesh Chingle ◽  
William D. Lubell ◽  
Chiara Gamberi
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Critical Evaluation ◽  
Substantial Reduction ◽  
Surrounding Tissue ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Precise Knowledge ◽  
Drosophila Model ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited malady affecting 12.5 million people worldwide. Therapeutic options to treat PKD are limited, due in part to lack of precise knowledge of underlying pathological mechanisms. Mimics of the second mitochondria-derived activator of caspases (Smac) have exhibited activity as antineoplastic agents and reported recently to ameliorate cysts in a murine ADPKD model, possibly by differentially targeting cystic cells and sparing the surrounding tissue. A first-in-kind Drosophila PKD model has now been employed to probe further the activity of novel Smac mimics. Substantial reduction of cystic defects was observed in the Malpighian (renal) tubules of treated flies, underscoring mechanistic conservation of the cystic pathways and potential for efficient testing of drug prototypes in this PKD model. Moreover, the observed differential rescue of the anterior and posterior tubules overall, and within their physiologically diverse intermediate and terminal regions implied a nuanced response in distinct tubular regions contingent upon the structure of the Smac mimic. Knowledge gained from studying Smac mimics reveals the capacity for the Drosophila model to precisely probe PKD pharmacology highlighting the value for such critical evaluation of factors implicated in renal function and pathology.

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 The cell biology of polycystic kidney disease

2010 ◽  
Vol 191 (4) ◽  
pp. 701-710 ◽  
Author(s):  
Hannah C. Chapin ◽  
Michael J. Caplan
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cell Biology ◽  
Fluid Transport ◽  
Genetic Disorder ◽  
Growth Control ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Renal Epithelial Cell ◽  
Autosomal Dominant Polycystic Kidney

Polycystic kidney disease is a common genetic disorder in which fluid-filled cysts displace normal renal tubules. Here we focus on autosomal dominant polycystic kidney disease, which is attributable to mutations in the PKD1 and PKD2 genes and which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis. The mechanisms that connect the underlying genetic defects to disease pathogenesis are poorly understood, but their exploration is shedding new light on interesting cell biological processes and suggesting novel therapeutic targets.

scholarly journals KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results

2020 ◽  
Vol 51 (6) ◽  
pp. 473-479
Author(s):  
Benjamin R. Griffin ◽  
Zhiying You ◽  
Lama Noureddine ◽  
Berenice Gitomer ◽  
Loni Perrenoud ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Progression ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Mixed Effects ◽  
Kidney Volume ◽  
Renal Tubules ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Over Time

Background: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. Methods: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. Results: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. Conclusion: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

scholarly journals Giant cystic degeneration of a uterine leiomyoma in a patient with autosomal dominant polycystic kidney disease

2016 ◽  
Vol 10 ◽  
pp. 1-3 ◽  
Author(s):  
Katrin Arnolds ◽  
Emily Senderey ◽  
Michael L. Sprague ◽  
Rodolfo Blandon ◽  
Diane L. Carlson ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Uterine Leiomyoma ◽  
Autosomal Dominant ◽  
Cystic Degeneration ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes

2020 ◽  
Vol 22 (8) ◽  
pp. 1374-1383
Author(s):  
Ria Schönauer ◽  
Sebastian Baatz ◽  
Melanie Nemitz-Kliemchen ◽  
Valeska Frank ◽  
Friederike Petzold ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Candidate Genes ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Potential Candidate ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney
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