scholarly journals Effect of Reducing Ataxia-Telangiectasia Mutated (ATM) in Experimental Autosomal Dominant Polycystic Kidney Disease

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 532
Author(s):  
Jennifer Q. J. Zhang ◽  
Sayanthooran Saravanabavan ◽  
Gopala K. Rangan
Keyword(s):  
Kidney Disease ◽  
Autosomal Dominant ◽  
Cyst Formation ◽  
Ataxia Telangiectasia Mutated ◽  
Polycystic Kidney ◽  
Kidney Cyst ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

The DNA damage response (DDR) pathway is upregulated in autosomal dominant polycystic kidney disease (ADPKD) but its functional role is not known. The ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) protein kinases are key proximal transducers of the DDR. This study hypothesized that reducing either ATM or ATR attenuates kidney cyst formation and growth in experimental ADPKD. In vitro, pharmacological ATM inhibition by AZD0156 reduced three-dimensional cyst growth in MDCK and human ADPKD cells by up to 4.4- and 4.1-fold, respectively. In contrast, the ATR inhibitor, VE-821, reduced in vitro MDCK cyst growth but caused dysplastic changes. In vivo, treatment with AZD0156 by oral gavage for 10 days reduced renal cell proliferation and increased p53 expression in Pkd1RC/RC mice (a murine genetic ortholog of ADPKD). However, the progression of cystic kidney disease in Pkd1RC/RC mice was not altered by genetic ablation of ATM from birth, in either heterozygous (Pkd1RC/RC/Atm+/−) or homozygous (Pkd1RC/RC/Atm−/−) mutant mice at 3 months. In conclusion, despite short-term effects on reducing renal cell proliferation, chronic progression was not altered by reducing ATM in vivo, suggesting that this DDR kinase is dispensable for kidney cyst formation in ADPKD.

scholarly journals Role of DNA-Dependent Protein Kinase in Mediating Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

2021 ◽  
Vol 22 (19) ◽  
pp. 10512
Author(s):  
Ashley N. Chandra ◽  
Sayanthooran Saravanabavan ◽  
Gopala K. Rangan
Keyword(s):  
Protein Kinase ◽  
Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Dependent Protein Kinase ◽  
Kidney Cyst ◽  
Dependent Protein ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein involved in DNA damage response (DDR) signaling that may mediate kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) due to its pleiotropic effects on proliferation and survival. To test this hypothesis, the expression of DNA-PK in human ADPKD and the in vitro effects of DNA-PK inhibition in a three-dimensional model of Madin-Darby Canine Kidney (MDCK) cyst growth and human ADPKD cells were assessed. In human ADPKD, the mRNA expression for all three subunits of the DNA-PK complex was increased, and using immunohistochemistry, the catalytic subunit (DNA-PKcs) was detected in the cyst lining epithelia of human ADPKD, in a focal manner. In vitro, NU7441 (a DNA-PK kinase inhibitor) reduced MDCK cyst growth by up to 52% after long-term treatment over 6–12 days. Although human ADPKD cell lines (WT9-7/WT9-12) did not exhibit synthetic lethality in response to DNA-PK kinase inhibition compared to normal human kidney cells (HK-2), the combination of low-dose NU7441 enhanced the anti-proliferative effects of sirolimus in WT9-7 and WT9-12 cells by 17 ± 10% and 11 ± 7%, respectively. In conclusion, these preliminary data suggest that DNA-PK mediates kidney cyst growth in vivo without a synthetically lethal interaction, conferring cell-specificity in human ADPKD cells. NU7441 enhanced the anti-proliferative effects of rapamycin complex 1 inhibitors, but the effect was modest.

scholarly journals An Overview of In Vivo and In Vitro Models for Autosomal Dominant Polycystic Kidney Disease: A Journey from 3D-Cysts to Mini-Pigs

2020 ◽  
Vol 21 (12) ◽  
pp. 4537
Author(s):  
Svenja Koslowski ◽  
Camille Latapy ◽  
Pierrïck Auvray ◽  
Marc Blondel ◽  
Laurent Meijer
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
In Vitro Models ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Stage Renal Disease ◽  
End Stage

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable cause of end stage renal disease and, as of today, only a single moderately effective treatment is available for patients. Even though ADPKD research has made huge progress over the last decades, the precise disease mechanisms remain elusive. However, a wide variety of cellular and animal models have been developed to decipher the pathophysiological mechanisms and related pathways underlying the disease. As none of these models perfectly recapitulates the complexity of the human disease, the aim of this review is to give an overview of the main tools currently available to ADPKD researchers, as well as their main advantages and limitations.

A role for CFTR in human autosomal dominant polycystic kidney disease

1996 ◽  
Vol 270 (1) ◽  
pp. C389-C399 ◽  
Author(s):  
K. Hanaoka ◽  
O. Devuyst ◽  
E. M. Schwiebert ◽  
P. D. Wilson ◽  
W. B. Guggino
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Primary Cultures ◽  
Cyst Formation ◽  
Disulfonic Acid ◽  
Polycystic Kidney ◽  
Acid Sensitivity ◽  
Autosomal Dominant Polycystic Kidney

Human autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal dominant hereditary disorder characterized by enormous renal enlargement and the development of multiple cysts originating from nephrons. We investigated the pathogenesis of cyst formation in ADPKD by using patch-clamp and immunocytochemical techniques. Adenosine 3',5'-cyclic monophosphate-activated Cl- currents are present in primary cultures of ADPKD cells and have characteristics such as a linear current-voltage relation, insensitivity to 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, sensitivity to glibenclamide and diphenylamine carboxylic acid, and an anion selectivity sequence of Br- > Cl- > I- > glutamate, all of which are identical to cystic fibrosis transmembrane conductance regulator (CFTR). With the use of CFTR antibodies raised against the regulatory and first nucleotide-binding domains, CFTR was detected in primary cultures of ADPKD cells. Similar results were obtained in vivo in cyst-lining epithelial cells in ADPKD kidneys, where staining was seen associated with the apical membrane regions. These data indicate that the CFTR Cl- channel exists in apical membranes of ADPKD cells and may play an important role in cyst formation or enlargement.

scholarly journals The tyrosine-kinase inhibitor Nintedanib ameliorates autosomal-dominant polycystic kidney disease

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Abeda Jamadar ◽  
Sreenath M. Suma ◽  
Sijo Mathew ◽  
Timothy A. Fields ◽  
Darren P. Wallace ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Kidney Disease ◽  
Autosomal Dominant ◽  
Renal Cyst ◽  
Growth Factor Receptor ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

AbstractAutosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and is characterized by progressive growth of fluid-filled cysts. Growth factors binding to receptor tyrosine kinases (RTKs) stimulate cell proliferation and cyst growth in PKD. Nintedanib, a triple RTK inhibitor, targets the vascular endothelial growth-factor receptor (VEGFR), platelet-derived growth-factor receptor (PDGFR), and fibroblast growth-factor receptor (FGFR), and is an approved drug for the treatment of non-small-cell lung carcinoma and idiopathic lung fibrosis. To determine if RTK inhibition using nintedanib can slow ADPKD progression, we tested its effect on human ADPKD renal cyst epithelial cells and myofibroblasts in vitro, and on Pkd1f/fPkhd1Cre and Pkd1RC/RC, orthologous mouse models of ADPKD. Nintedanib significantly inhibited cell proliferation and in vitro cyst growth of human ADPKD renal cyst epithelial cells, and cell viability and migration of human ADPKD renal myofibroblasts. Consistently, nintedanib treatment significantly reduced kidney-to-body-weight ratio, renal cystic index, cystic epithelial cell proliferation, and blood-urea nitrogen levels in both the Pkd1f/fPkhd1Cre and Pkd1RC/RC mice. There was a corresponding reduction in ERK, AKT, STAT3, and mTOR activity and expression of proproliferative factors, including Yes-associated protein (YAP), c-Myc, and Cyclin D1. Nintedanib treatment significantly reduced fibrosis in Pkd1RC/RC mice, but did not affect renal fibrosis in Pkd1f/fPkhd1Cre mice. Overall, these results suggest that nintedanib may be repurposed to effectively slow cyst growth in ADPKD.

scholarly journals The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease

2020 ◽  
Author(s):  
Shirin V. Sundar ◽  
Xia Zhou ◽  
Brenda S. Magenheimer ◽  
Gail A. Reif ◽  
Darren P. Wallace ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Cell Motility ◽  
Polycystic Kidney Disease ◽  
Short Circuit ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Cyst Growth

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl− secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50 of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl− channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1flox/flox:Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl− secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease

NEJM Evidence ◽  
2021 ◽  
Author(s):  
Gopala K. Rangan ◽  
Annette T.Y. Wong ◽  
Alexandra Munt ◽  
Jennifer Q.J. Zhang ◽  
Sayanthooran Saravanabavan ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Arginine Vasopressin ◽  
Autosomal Dominant ◽  
Urine Osmolality ◽  
Polycystic Kidney ◽  
Vasopressin Release ◽  
Kidney Cyst ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

In patients with autosomal dominant polycystic kidney disease (ADPKD), drinking more water could potentially reduce urine osmolality and suppress arginine vasopressin release and decrease the rate of kidney cyst growth and its associated organ dysfunction. In a 3-year trial, adults with ADPKD randomized to drink more water so as to lower urine osmolality did not have slower kidney growth than did a group who drank water as they wished.

Quercetin inhibits renal cyst growth in vitro and via parenteral injection in a polycystic kidney disease mouse model

2018 ◽  
Vol 9 (1) ◽  
pp. 389-396 ◽  
Author(s):  
Yangyang Zhu ◽  
Tian Teng ◽  
Hu Wang ◽  
Hao Guo ◽  
Lei Du ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Renal Cyst ◽  
Monogenic Disease ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by massive enlargement of fluid-filled cysts in the kidney.

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.

Olive leaf extract counteracts cell proliferation and cyst growth in an in vitro model of autosomal dominant polycystic kidney disease

2018 ◽  
Vol 9 (11) ◽  
pp. 5925-5935
Author(s):  
G. Toteda ◽  
D. Vizza ◽  
S. Lupinacci ◽  
A. Perri ◽  
M. F. Scalise ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
In Vitro Model ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Vitro Model ◽  
Cyst Growth ◽  
Progressive Enlargement

–Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts, leading to chronic kidney disease.

scholarly journals Applications of Herbal Medicine to Treat Autosomal Dominant Polycystic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Guangying Shao ◽  
Shuai Zhu ◽  
Baoxue Yang
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Herbal Medicines ◽  
Renal Cysts ◽  
Cordyceps Sinensis ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary kidney disease, which is featured by progressively enlarged bilateral fluid-filled cysts. Enlarging cysts destroy the structure of nephrons, ultimately resulting in the loss of renal function. Eventually, ADPKD develops into end-stage renal disease (ESRD). Currently, there is no effective drug therapy that can be safely used clinically. Patients progressed into ESRD usually require hemodialysis and kidney transplant, which is a heavy burden on both patients and society. Therefore, looking for effective therapeutic drugs is important for treating ADPKD. In previous studies, herbal medicines showed their great effects in multiple diseases, such as cancer, diabetes and mental disorders, which also might play a role in ADPKD treatment. Currently, several studies have reported that the compounds from herbal medicines, such as triptolide, curcumin, ginkolide B, steviol, G. lucidum triterpenoids, Celastrol, saikosaponin-d, Sparganum stoloniferum Buch.-Ham and Cordyceps sinensis, contribute to the inhibition of the development of renal cysts and the progression of ADPKD, which function by similar or different mechanisms. These studies suggest that herbal medicines could be a promising type of drugs and can provide new inspiration for clinical therapeutic strategy for ADPKD. This review summarizes the pharmacological effects of the herbal medicines on ADPKD progression and their underlying mechanisms in both in vivo and in vitro ADPKD models.

Sign in / Sign up

Export Citation Format

Share Document