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 A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease

2019 ◽  
Vol 317 (1) ◽  
pp. F187-F196 ◽  
Author(s):  
Sara J. Holditch ◽  
Carolyn N. Brown ◽  
Daniel J. Atwood ◽  
Andrew M. Lombardi ◽  
Khoa N. Nguyen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Autosomal Dominant ◽  
Kinase Inhibitor ◽  
Polycystic Kidney ◽  
Mtor Kinase ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. Sirolimus indirectly inhibits mTORC1. Novel mTOR kinase inhibitors directly inhibit mTOR kinase, resulting in the inhibition of mTORC1 and mTORC2. The aim of the present study was to determine the effects of sirolimus versus the mTOR kinase inhibitor torin2 on cyst growth and kidney function in the Pkd1 p.R3277C ( Pkd1RC/RC) mouse model, a hypomorphic Pkd1 model orthologous to the human condition, and to determine the effects of sirolimus versus torin2 on mTORC1 and mTORC2 signaling in PKD1−/− cells and in the kidneys of Pkd1RC/RC mice. In vitro, both inhibitors reduced mTORC1 and mTORC2 phosphorylated substrates and negatively impacted cellular metabolic activity, as measured by MTT assay. Pkd1RC/RC mice were treated with sirolimus or torin2 from 50 to 120 days of age. Torin2 was as effective as sirolimus in decreasing cyst growth and improving loss of kidney function. Both sirolimus and torin2 decreased phosphorylated S6 protein, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1, phosphorylated Akt, and proliferation in Pkd1RC/RC kidneys. In conclusion, torin2 and sirolimus were equally effective in decreasing cyst burden and improving kidney function and mediated comparable effects on mTORC1 and mTORC2 signaling and proliferation in the Pkd1RC/RC kidney.

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.

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 Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease

2013 ◽  
Vol 110 (31) ◽  
pp. 12786-12791 ◽  
Author(s):  
T. Seeger-Nukpezah ◽  
D. A. Proia ◽  
B. L. Egleston ◽  
A. S. Nikonova ◽  
T. Kent ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Hsp90 Chaperone ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth
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