scholarly journals Periostin induces proliferation of human autosomal dominant polycystic kidney cells through αV-integrin receptor

2008 ◽  
Vol 295 (5) ◽  
pp. F1463-F1471 ◽  
Author(s):  
Darren P. Wallace ◽  
Megan T. Quante ◽  
Gail A. Reif ◽  
Emily Nivens ◽  
Farhana Ahmed ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Plasma Membranes ◽  
Autosomal Dominant ◽  
Human Kidney ◽  
Polycystic Kidney ◽  
Normal Human Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Lining ◽  
Cyst Growth

Progressive renal enlargement due to the growth of innumerable fluid-filled cysts is a central pathophysiological feature of autosomal dominant polycystic kidney disease (ADPKD). These epithelial neoplasms enlarge slowly and damage noncystic parenchyma by mechanisms that have not been clearly defined. In a microarray analysis of cultured human ADPKD cyst epithelial cells, periostin mRNA was overexpressed 15-fold compared with normal human kidney (NHK) cells. Periostin, initially identified in osteoblasts, is not expressed in normal adult kidneys but is expressed transiently during renal development. We found periostin in cyst-lining cells in situ in the extracellular matrix adjacent to the cysts and within cyst fluid. ADPKD cells secreted periostin across luminal and basolateral plasma membranes. Periostin increased proliferation of cyst epithelial cells 27.9 ± 3.1% ( P < 0.001) above baseline and augmented in vitro cyst growth but did not affect proliferation of normal renal cells. Expression of αV-integrin, a periostin receptor, was ninefold higher in ADPKD cells compared with NHK cells, and antibodies that block αV-integrin inhibited periostin-induced cell proliferation. We conclude that periostin is a novel autocrine mitogen secreted by mural epithelial cells with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD.

scholarly journals Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Ding ◽  
Linda Xiaoyan Li ◽  
Peter C. Harris ◽  
Junwei Yang ◽  
Xiaogang Li
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Extracellular Vesicles ◽  
Autosomal Dominant ◽  
Therapeutic Potential ◽  
Polycystic Kidney ◽  
Renal Epithelial Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a “cystic extracellular vesicles/exosomes theory”. We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.

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 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.

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 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.

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 Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248400
Author(s):  
Jennifer Q. J. Zhang ◽  
Sayanthooran Saravanabavan ◽  
Kai Man Cheng ◽  
Aarya Raghubanshi ◽  
Ashley N. Chandra ◽  
...  
Keyword(s):  
Sodium Nitrate ◽  
Autosomal Dominant ◽  
Renal Cyst ◽  
High Dose ◽  
Polycystic Kidney ◽  
Nitrate Supplementation ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9–7, WT 9–12), and the effect of L-arginine on anin vitromodel of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygousPkd1RC/RCmice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.1, 1 or 10 mmol/kg/day), or sodium chloride (vehicle; 10 mmol/kg/day), supplemented drinking water from postnatal month 1 to 9 (n = 12 per group).In vitro, intracellular NO, as assessed by DAF-2/DA fluorescence, was reduced by >70% in human ADPKD cell lines, and L-arginine and the NO donor, sodium nitroprusside, both attenuatedin vitrocyst growth by up to 18%. In contrast, inPkd1RC/RCmice, sodium nitrate supplementation increased serum nitrate/nitrite levels by ~25-fold in the high dose group (P<0.001), but kidney enlargement and percentage cyst area was not altered, regardless of dose. In conclusion, L-arginine has mild direct efficacy on reducing renal cyst growthin vitro, whereas long-term sodium nitrate supplementation was ineffectivein vivo. These data suggest that the bioconversion of dietary nitrate to NO by the entero-salivary pathway may not be sufficient to influence the progression of renal cyst growth in ADPKD.

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