FP058AN OLIVE LEAF EXTRACT REDUCES INFLAMMATION AND FIBROSIS IN AN IN VITRO MODEL OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

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.

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

Cell Death and Disease ◽

10.1038/s41419-021-04248-9 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms221910512 ◽

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.

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A chalcone derivative retards renal cyst enlargement by inhibiting fluid secretion and cell proliferation in an in vitro model of polycystic kidney disease

Clinical and Experimental Nephrology ◽

10.1007/s10157-021-02080-1 ◽

2021 ◽

Author(s):

Peerachat Veeraphan ◽

Warinthorn Chavasiri ◽

Chatchai Muanprasat ◽

Varanuj Chatsudthipong ◽

Chaowalit Yuajit

Keyword(s):

Cell Proliferation ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

In Vitro Model ◽

Renal Cyst ◽

Fluid Secretion ◽

Polycystic Kidney ◽

Chalcone Derivative ◽

Vitro Model

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

Food & Function ◽

10.1039/c7fo01253e ◽

2018 ◽

Vol 9 (1) ◽

pp. 389-396 ◽

Cited By ~ 6

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.

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