scholarly journals Pioglitazone Attenuates Cystic Burden in the PCK Rodent Model of Polycystic Kidney Disease

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Bonnie L. Blazer-Yost ◽  
Julie Haydon ◽  
Tracy Eggleston-Gulyas ◽  
Jey-Hsin Chen ◽  
Xiaofang Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Genetic Disorder ◽  
Hepatic Cyst ◽  
Rodent Model ◽  
Mrna Levels ◽  
Polycystic Kidney ◽  
Duct Cyst ◽  
Cyst Aspiration ◽  
Cyst Growth

Polycystic kidney disease (PKD) is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney tubules and liver bile ducts. Currently, the clinical management of PKD is limited to cyst aspiration, surgical resection or organ transplantation. Based on an observation that PPARγagonists such as pioglitazone and rosiglitazone decrease mRNA levels of aCl−transport protein, CFTR (cystic fibrosis transmembrane conductance regulator), and theCl−secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγagonists will inhibit cyst growth. The current studies show that a 7- or 14-week pioglitazone feeding regimen inhibits renal and hepatic bile duct cyst growth in the PCK rat, a rodent model orthologous to human PKD. These studies provide proof of concept for the mechanism of action of the PPARγagonists and suggest that this class of drugs may be effective in controlling both renal and hepatic cyst growth and fibrosis in PKD.

scholarly journals In vitro 3D phenotypic drug screen identifies celastrol as an effective in vivo inhibitor of polycystic kidney disease

2019 ◽  
Vol 12 (8) ◽  
pp. 644-653 ◽  
Author(s):  
Tijmen H Booij ◽  
Wouter N Leonhard ◽  
Hester Bange ◽  
Kuan Yan ◽  
Michiel Fokkelman ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Genetic Disorder ◽  
Screening Method ◽  
Renal Cysts ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Cyst Growth

Abstract Polycystic kidney disease (PKD) is a prevalent genetic disorder, characterized by the formation of kidney cysts that progressively lead to kidney failure. The currently available drug tolvaptan is not well tolerated by all patients and there remains a strong need for alternative treatments. The signaling rewiring in PKD that drives cyst formation is highly complex and not fully understood. As a consequence, the effects of drugs are sometimes difficult to predict. We previously established a high throughput microscopy phenotypic screening method for quantitative assessment of renal cyst growth. Here, we applied this 3D cyst growth phenotypic assay and screened 2320 small drug-like molecules, including approved drugs. We identified 81 active molecules that inhibit cyst growth. Multi-parametric phenotypic profiling of the effects on 3D cultured cysts discriminated molecules that showed preferred pharmacological effects above genuine toxicological properties. Celastrol, a triterpenoid from Tripterygium Wilfordii, was identified as a potent inhibitor of cyst growth in vitro. In an in vivo iKspCre-Pkd1lox,lox mouse model for PKD, celastrol inhibited the growth of renal cysts and maintained kidney function.

scholarly journals Novel Potential Application of Chitosan Oligosaccharide for Attenuation of Renal Cyst Growth in the Treatment of Polycystic Kidney Disease

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5589 ◽  
Author(s):  
Nutthapoom Pathomthongtaweechai ◽  
Sunhapas Soodvilai ◽  
Rath Pichyangkura ◽  
Chatchai Muanprasat
Keyword(s):  
Protein Kinase ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Renal Cyst ◽  
Kidney Diseases ◽  
Biological Activities ◽  
Genetic Disorder ◽  
Chitosan Oligosaccharide ◽  
Polycystic Kidney ◽  
Cyst Growth

Chitosan oligosaccharide (COS), a natural polymer derived from chitosan, exerts several biological activities including anti-inflammation, anti-tumor, anti-metabolic syndrome, and drug delivery enhancer. Since COS is vastly distributed to kidney and eliminated in urine, it may have a potential advantage as the therapeutics of kidney diseases. Polycystic kidney disease (PKD) is a common genetic disorder characterized by multiple fluid-filled cysts, replacing normal renal parenchyma and leading to impaired renal function and end-stage renal disease (ESRD). The effective treatment for PKD still needs to be further elucidated. Interestingly, AMP-activated protein kinase (AMPK) has been proposed as a drug target for PKD. This study aimed to investigate the effect of COS on renal cyst enlargement and its underlying mechanisms. We found that COS at the concentrations of 50 and 100 µg/mL decreased renal cyst growth without cytotoxicity, as measured by MTT assay. Immunoblotting analysis showed that COS at 100 µg/mL activated AMPK, and this effect was abolished by STO-609, a calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ) inhibitor. Moreover, COS elevated the level of intracellular calcium. These results suggest that COS inhibits cyst progression by activation of AMPK via CaMKKβ. Therefore, COS may hold the potential for pharmaceutical application in PKD.

Everolimus Retards Cyst Growth and Preserves Kidney Function in a Rodent Model for Polycystic Kidney Disease

2007 ◽  
Vol 30 (4) ◽  
pp. 253-259 ◽  
Author(s):  
Ming Wu ◽  
Patricia R. Wahl ◽  
Michel Le Hir ◽  
Ying Wäckerle-Men ◽  
Rudolf P. Wüthrich ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Rodent Model ◽  
Polycystic Kidney ◽  
Cyst Growth

scholarly journals Quinomycin A reduces cyst progression in Polycystic Kidney Disease

2020 ◽  
Author(s):  
Priyanka S Radadiya ◽  
Mackenzie M Thornton ◽  
Brenda Magenheimer ◽  
Dharmalingam Subramaniam ◽  
Pamela V Tran ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cancer Progression ◽  
Collecting Duct ◽  
Genetic Disorder ◽  
Notch Pathway ◽  
Collagen Gel ◽  
Protective Effects ◽  
Polycystic Kidney ◽  
Duct Cyst

AbstractPolycystic kidney disease (PKD) is a genetic disorder that affects cilia homeostasis and causes progressive growth of tubular-derived cysts within the kidney. Efforts to find safer drugs for PKD have increased in the past few years after the successful launch of tolvaptan, the first approved drug to combat autosomal dominant PKD progression. Here we investigate the effects of Quinomycin A on progression of PKD. Quinomycin A is a bis-intercalator peptide that has previously shown to be effective against cancer progression. Quinomycin A treatment decreased cyst progression of human ADPKD primary renal epithelial cells grown in a 3D collagen gel to form cysts. In an orthologous mouse model of PKD, Quinomycin A administration reduced kidney to body weight ratios, and reduced cystogenesis. This was accompanied by decreased cell proliferation and fibrosis. Quinomycin treatments efficiently reduced the expression of Notch pathway proteins, RBPjk and HeyL in kidneys of PKD mice. Interestingly, Quinomycin treatments also normalized cilia lengths of collecting duct cyst-lining renal epithelia of PKD mice. This is the first preclinical study to our knowledge that demonstrates Quinomycin A has protective effects against PKD progression, in part by reducing Notch signaling and renal epithelial cilia lengths. Our findings suggest Quinomycin A has potential therapeutic value for PKD patients.

scholarly journals Chronic exercise protects against the progression of renal cyst growth and dysfunction in rats with polycystic kidney disease

2021 ◽  
Author(s):  
Jiahe Qiu ◽  
Yoichi Sato ◽  
Lusi Xu ◽  
Takahiro Miura ◽  
Masahiro Kohzuki ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Renal Cyst ◽  
Genetic Disorder ◽  
Exercise Group ◽  
Chronic Exercise ◽  
Polycystic Kidney ◽  
Camp Content ◽  
Fatty Acid Binding ◽  
Cyst Growth

AbstractIntroductionPolycystic kidney disease (PKD) is a genetic disorder characterized by the progressive enlargement of renal epithelial cysts and renal dysfunction. Previous studies have reported the beneficial effects of chronic exercise on chronic kidney disease. However, the effects of chronic exercise have not been fully examined in PKD patients or models. The effects of chronic exercise on the progression of PKD were investigated in a polycystic kidney (PCK) rat model.MethodsSix-week-old male PCK rats were divided into a sedentary group and an exercise group. The exercise group underwent forced treadmill exercise for 12 weeks (28 m/min, 60 min/day, 5 days/week). After 12 weeks, kidney function and histology were examined, protein expressions were analyzed, and signaling cascades of PKD were examined.ResultsChronic exercise reduced the excretion of urinary protein, liver-type fatty acid-binding protein, plasma creatinine, urea nitrogen, and increased plasma irisin and urinary arginine vasopressin (AVP) excretion. Chronic exercise also slowed renal cyst growth, glomerular damage, and interstitial fibrosis, and led to reduced Ki-67 expression. Chronic exercise had no effect on cAMP content but decreased the renal expression of B-Raf and reduced the phosphorylation of extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), and S6.ConclusionChronic exercise slows renal cyst growth and damage in PCK rats, despite increasing AVP, with down-regulation of the cAMP/B-Raf/ERK and mTOR/S6 pathways in the kidney of PCK rats.

scholarly journals Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-4
Author(s):  
L. Friedrich ◽  
F. Barbey ◽  
M. Pascual ◽  
J.-P. Venetz
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Clinical Studies ◽  
Mtor Inhibitor ◽  
Autosomal Dominant ◽  
Mtor Inhibitors ◽  
Hepatic Cyst ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.

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