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

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

10.1101/2020.09.09.258160 ◽

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.

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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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Role of CFTR in Autosomal Recessive Polycystic Kidney Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.v124719 ◽

2001 ◽

Vol 12 (4) ◽

pp. 719-725

Author(s):

KOICHI NAKANISHI ◽

WILLIAM E. SWEENEY ◽

KATHERINE MACRAE DELL ◽

CALVIN U. COTTON ◽

ELLIS D. AVNER

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Murine Model ◽

Autosomal Recessive ◽

Renal Cyst ◽

Fluid Secretion ◽

Cyst Formation ◽

Polycystic Kidney ◽

Cftr Protein

Abstract. An extensive body of in vitro data implicates epithelial chloride secretion, mediated through cystic fibrosis transmembrane conductance regulator (CFTR) protein, in generating or maintaining fluid filled cysts in MDCK cells and in human autosomal dominant polycystic kidney disease (ADPKD). In contrast, few studies have addressed the pathophysiology of fluid secretion in cyst formation and enlargement in autosomal recessive polycystic kidney disease (ARPKD). Murine models of targeted disruptions or deletions of specific genes have created opportunities to examine the role of individual gene products in normal development and/or disease pathophysiology. The creation of a murine model of CF, which lacks functional CFTR protein, provides the opportunity to determine whether CFTR activity is required for renal cyst formation in vivo. Therefore, this study sought to determine whether renal cyst formation could be prevented by genetic complementation of the BPK murine model of ARPKD with the CFTR knockout mouse. The results of this study reveal that in animals that are homozygous for the cystic gene (bpk), the lack of functional CFTR protein on the apical surface of cystic epithelium does not provide protection against cyst growth and subsequent decline in renal function. Double mutant mice (bpk -/-; cftr -/-) developed massively enlarged kidneys and died, on average, 7 d earlier than cystic, non-CF mice (bpk -/-; cftr +/±). This suggests fundamental differences in the mechanisms of transtubular fluid secretion in animal models of ARPKD compared with ADPKD.

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz106.fp058 ◽

2019 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Giuseppina Toteda ◽

Anna Perri ◽

Simona Lupinacci ◽

Donatella Vizza ◽

Antonella La Russa ◽

...

Keyword(s):

Kidney Disease ◽

Leaf Extract ◽

In Vitro Model ◽

Autosomal Dominant ◽

Olive Leaf ◽

Polycystic Kidney ◽

Olive Leaf Extract ◽

Autosomal Dominant Polycystic Kidney ◽

Vitro Model

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Restoring multidrug resistance-associated protein 3 attenuates cell proliferation in the polycystic kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00159.2014 ◽

2015 ◽

Vol 308 (9) ◽

pp. F1004-F1011 ◽

Cited By ~ 2

Author(s):

EunSun Chang ◽

Eun Young Park ◽

Yu mi Woo ◽

Duk-Hee Kang ◽

Young-Hwan Hwang ◽

...

Keyword(s):

Cell Proliferation ◽

Renal Function ◽

Multidrug Resistance ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Drug Targets ◽

Cyst Formation ◽

Polycystic Kidney ◽

Renal Epithelial Cell

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal proliferation of renal tubular epithelial cells, resulting in the loss of renal function. Despite identification of the genes responsible for ADPKD, few effective drugs are currently available for the disease. Thus finding additional effective drug targets is necessary. The functions of multidrug- resistance-associated protein 3 (MRP3) have been reported only in the field of drug resistance, and the renal functions of MRP3 are mostly unknown. In this study, we found that MRP3 was significantly downregulated in kidneys of human patients with ADPKD and polycystic kidney disease (PKD) mouse models. Our results suggest that downregulated MRP3 stimulated renal epithelial cell proliferation through the B-Raf/MEK/ERK signaling pathway. In contrast, we found that restoring MRP3 reduced cell proliferation and cystogenesis in vitro. These results suggest that the renal function of MRP3 is related to renal cell proliferation and cyst formation and that restoring MRP3 may be an effective therapeutic approach for PKD.

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