The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Vicente E Torres - One of the best experts on this subject based on the ideXlab platform.
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Impaired Hedgehog-Gli1 Pathway Activity Underlies the Vascular Phenotype of Polycystic Kidney Disease.
Hypertension (Dallas Tex. : 1979), 2020Co-Authors: Federico Franchi, Vicente E Torres, Karen M. Peterson, Katherine Quandt, David Domnick, Timothy L. Kline, Michaela Olthoff, Mojtaba Parvizi, Ezequiel J. Tolosa, Peter C. HarrisAbstract:Polycystic kidney disease (PKD) has been linked to abnormal structure/function of ciliary proteins, leading to renal dysfunction. Recently, attention has been focused in the significant vascular abnormalities associated with PKD, but the mechanisms underlying this phenomenon remain elusive. Here, we seek to define the molecular events regulating the angiogenic imbalance observed in PKD. Using micro computed tomography (n=7) and protein expression analysis (n=5), we assessed the vascular density and the angiogenic profile of noncystic organs in a well-established PKD Rat model (Polycystic Kidney-PCK Rat). Heart and lungs of PCK Rats have reduced vascular density and decreased expression of angiogenic factors compared with wild type. Similarly, PCK-vascular smooth muscle cells (VSMCs; n=4) exhibited lower levels of vascular markers. Then, using small interfering RNA (n=4), we determined the role of the ciliary protein fibrocystin in wild type-VSMCs, a critical component/regulator of vascular structure and function. Reduction of fibrocystin in wild type-VSMCs (n=4) led to an abnormal angiogenic potential similar to that observed in PCK-VSMCs. Furthermore, we investigated the involvement of the hedgehog signaling, a pathway closely linked to the primary cilium and associated with vascular development, in PKD. Mechanistically, we demonstRated that impairment of the hedgehog signaling mediates, in part, this abnormal angiogenic phenotype. Lastly, overexpression of Gli1 in PCK-VSMCs (n=4) restored the expression levels of proangiogenic molecules. Our data support a critical role of fibrocystin in the abnormal vascular phenotype of PKD and indicate that a dysregulation of hedgehog may be responsible, at least in part, for these vascular deficiencies.
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New Insights, Treatments, and Management StRategies for ADPKD: Role of Vasopressin Antagonists
2016Co-Authors: Vicente E TorresAbstract:AlteRations in intracellular calcium homeostasis and cyclic adenosine 3,5-phosphate likely underlie the increased cell prolifeRation and fluid secretion in polycystic kidney disease. Hormone receptors that affect cyclic adenosine 3,5-phosphate and are preferentially expressed in affected tissues are logical treatment targets. There is a sound Rationale for considering the arginine vasopressin V2 receptor as a target. The arginine vasopressin V2 receptor antagonists OPC-31260 and tolvaptan inhibit the development of polycystic kidney disease in cpk mice and in three animal orthologs to human autosomal recessive polycystic kidney disease (PCK Rat), autosomal dominant polycystic kidney disease (Pkd2/WS25 mice), and nephronoph-thisis (pcy mouse). PCK Rats that are homozygous for an arginine vasopressin mutation and lack circulating vasopressin are markedly protected. AdministRation of V2 receptor agonist 1-deamino-8-D-arginine vasopressin to these animals completely recovers the cystic phenotype. AdministRation of 1-deamino-8-D-arginine vasopressin to PCK Rats with normal arginine vasopressin aggravates the disease. Suppression of arginine vasopressin release by high water intake is protective. V2 receptor antagonists may have additional beneficial effects on hypertension and chronic kidney disease progression. A number of clinical studies in polycystic kidney disease have been performed or are currently active. The results of phase 2 and 2–3 studies indicate that tolvaptan seems to be safe and well toleRated in autosomal dominant polycystic kidney disease. A phase 3, placebo-controlled, double-blind study in 18- to 50-yr-old patients with autosomal dominant polycystic kidney disease and preserved renal function but relatively rapid progression, as indicated by a total kidney volume>750 ml, has been initiated
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the cleaved cytoplasmic tail of polycystin 1 regulates src dependent stat3 activation
Journal of The American Society of Nephrology, 2014Co-Authors: Jeffrey J Talbot, Vicente E Torres, Xiaofang Wang, Xuewen Song, Markus M Rinschen, Nicholas Doerr, Wells B Lariviere, Bernhard Schermer, York Pei, Thomas WeimbsAbstract:Polycystin-1 (PC1) mutations result in prolifeRative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Src-dependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30–mediated activation of Src/STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR- or IL-6–dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) Rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integRates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a prolifeRative response.
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doi:10.1155/2010/274376 Research Article Pioglitazone Attenuates Cystic Burden in the PCK Rodent Model of Polycystic Kidney Disease
2013Co-Authors: Bonnie L. Blazer-yost, Vincent H Gattone, Xiaofang Wang, Julie Haydon, Jeyhsin Chen, Tracy Eggleston-gulyas, Vicente E TorresAbstract:Copyright © 2010 Bonnie L. Blazer-Yost et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Polycystic kidney disease (PKD) is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney tubules and liver bile ducts. Currently, the clinical management of PKD is limited to cyst aspiRation, surgical resection or organ transplantation. Based on an observation that PPARγ agonists such as pioglitazone and rosiglitazone decrease mRNA levels of a Cl − transport protein, CFTR (cystic fibrosis transmembrane conductance regulator), and the Cl − secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7- or 14week pioglitazone feeding regimen inhibits renal and hepatic bile duct cyst growth in the PCK Rat, a rodent model orthologous to human PKD. These studies provide proof of concept for the mechanism of action of the PPARγ agonists and suggest that this class of drugs may be effective in controlling both renal and hepatic cyst growth and fibrosis in PKD. 1
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pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases
Hepatology, 2013Co-Authors: Tatyana V Masyuk, Sergio A Gradilone, Anatoliy I Masyuk, Jesus M Banales, Angela J Stroope, Brynn N Radtke, Bing Huang, Marie C Hogan, Vicente E TorresAbstract:Polycystic liver (PLD) and kidney (PKD) diseases are incurable genetic disorders linked to disturbances in many intracellular signaling pathways and cell functions.(1–3) One of the well-defined mechanisms involved in hepato-renal cystogenesis is increased accumulation of intracellular cAMP that triggers cell hyper-prolifeRation, cell cycle deregulation and fluid secretion. Basal cAMP levels in cholangiocytes are maintained by the coordinated functioning of: 1) secretin receptors (activation of which by secretin increases cAMP); 2) somatostatin receptors ([SSTRs], activation of which by somatostatin inhibits cAMP); 3) adenylyl cyclases (crucial for cAMP production); and 4) phosphodiesterases (critical for cAMP degradation).(1, 2) Activation of SSTRs induces multiple transduction pathways and mediates several cellular functions; however inhibition of cell prolifeRation is one of the major effects.(4, 5) Cholangiocytes express all five SSTRs (i.e., SSTR1 through 5).(6, 7) Importantly, targeting of SSTRs with synthetic somatostatin analogues in patients with PLD and PKD has limited but unequivocal benefit by reducing cyst growth.(3, 7–10) The natural SSTR ligand, somatostatin, is susceptible to proteolytic degradation and has a short half-life (~3 minutes) limiting its clinical utility.(5) Over the years, multiple stable somatostatin analogues have been developed. Octreotide [(OCT), Sandostatin®, SMS 201-95], a synthetic octapeptide with a half-life of 2 hours, was the first clinically introduced analogue. We and others have tested the effects of OCT in preclinical and clinical trials in PLD and PKD.(7–11) However, despite beneficial results (i.e., symptom relief and cyst reduction), changes in liver and kidney volumes in patients are modeRate; thus, additional pharmacologic approaches are needed. OCT binds with high affinity to SSTR2 and SSTR3, with modeRate affinity to SSTR5, and has no affinity to SSTR1 and SSTR4.(5, 12, 13) Since all five SSTRs coexist in cholangiocytes and renal epithelia(6, 7, 14), somatostatin analogues with higher binding affinity to a broader range of SSTRs might be more effective. Recently, cyclohexapeptide Pasireotide (PAS, SOM-230) has been evaluated experimentally and clinically for the treatment of different pathological conditions.(12, 13) PAS has a high affinity to SSTR1, SSTR2, SSTR3 and SSTR5 and a half-life of 12 hours.(12, 13, 15) Thus, we hypothesized that PAS should have more potent suppressive effects than OCT on cyst growth. We used in vitro and in vivo experimental systems and models to compare the effects of OCT and PAS on cAMP levels, cell prolifeRation, cell cycle distribution and hepatic cyst growth in vitro; and hepato-renal cystogenesis in two animal models of PLD and PKD, the PCK Rat and Pkd2WS25/− mice. Expression of SSTRs in control and cystic cholangiocytes was assessed under basal conditions and after treatment. In addition, we examined concentRations of IGF1 and VEGF in response to OCT and PAS since these growth factors are linked to indirect inhibitory action of somatostatin analogues and known to trigger hepato-renal cystogenesis via autocrine and paracrine mechanisms.(15–19) We show that PAS has stronger suppressive effects on hepato-renal cystogenesis compared to OCT and thus might be more beneficial than OCT in patients with PLD and PKD.
Yasuni Nakanuma - One of the best experts on this subject based on the ideXlab platform.
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activation of the pi3k mtor pathway is involved in cystic prolifeRation of cholangiocytes of the PCK Rat
PLOS ONE, 2014Co-Authors: Yasunori Sato, Shinichi Furubo, Kenichi Harada, Xiang Shan Ren, Motoko Sasaki, Jing Yu Song, Yasuni NakanumaAbstract:The polycystic kidney (PCK) Rat is an animal model of Caroli’s disease as well as autosomal recessive polycystic kidney disease (ARPKD). The signaling pathways involving the mammalian target of rapamycin (mTOR) are aberrantly activated in ARPKD. This study investigated the effects of inhibitors for the cell signaling pathways including mTOR on cholangiocyte prolifeRation of the PCK Rat. Cultured PCK cholangiocytes were treated with rapamycin and everolimus [inhibitors of mTOR complex 1 (mTOC1)], LY294002 [an inhibitor of phosphatidylinositol 3-kinase (PI3K)] and NVP-BEZ235 (an inhibitor of PI3K and mTORC1/2), and the cell prolifeRative activity was determined in relation to autophagy and apoptosis. The expression of phosphorylated (p)-mTOR, p-Akt, and PI3K was increased in PCK cholangiocytes compared to normal cholangiocytes. All inhibitors significantly inhibited the cell prolifeRative activity of PCK cholangiocytes, where NVP-BEZ235 had the most prominent effect. NVP-BEZ235, but not rapamycin and everolimus, further inhibited biliary cyst formation in the three-dimensional cell culture system. Rapamycin and everolimus induced apoptosis in PCK cholangiocytes, whereas NVP-BEZ235 inhibited cholangiocyte apoptosis. Notably, the autophagic response was significantly induced following the treatment with NVP-BEZ235, but not rapamycin and everolimus. Inhibition of autophagy using siRNA against protein-light chain3 and 3-methyladenine significantly increased the cell prolifeRative activity of PCK cholangiocytes treated with NVP-BEZ235. In vivo, treatment of the PCK Rat with NVP-BEZ235 attenuated cystic dilatation of the intrahepatic bile ducts, whereas renal cyst development was unaffected. These results suggest that the aberrant activation of the PI3K/mTOR pathway is involved in cystic prolifeRation of cholangiocytes of the PCK Rat, and inhibition of the pathway can reduce cholangiocyte prolifeRation via the mechanism involving apoptosis and/or autophagy.
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Activation of the PI3K/mTOR Pathway Is Involved in Cystic ProlifeRation of Cholangiocytes of the PCK Rat
PloS one, 2014Co-Authors: Xiang Shan Ren, Yasunori Sato, Shinichi Furubo, Kenichi Harada, Motoko Sasaki, Jing Yu Song, Yasuni NakanumaAbstract:The polycystic kidney (PCK) Rat is an animal model of Caroli’s disease as well as autosomal recessive polycystic kidney disease (ARPKD). The signaling pathways involving the mammalian target of rapamycin (mTOR) are aberrantly activated in ARPKD. This study investigated the effects of inhibitors for the cell signaling pathways including mTOR on cholangiocyte prolifeRation of the PCK Rat. Cultured PCK cholangiocytes were treated with rapamycin and everolimus [inhibitors of mTOR complex 1 (mTOC1)], LY294002 [an inhibitor of phosphatidylinositol 3-kinase (PI3K)] and NVP-BEZ235 (an inhibitor of PI3K and mTORC1/2), and the cell prolifeRative activity was determined in relation to autophagy and apoptosis. The expression of phosphorylated (p)-mTOR, p-Akt, and PI3K was increased in PCK cholangiocytes compared to normal cholangiocytes. All inhibitors significantly inhibited the cell prolifeRative activity of PCK cholangiocytes, where NVP-BEZ235 had the most prominent effect. NVP-BEZ235, but not rapamycin and everolimus, further inhibited biliary cyst formation in the three-dimensional cell culture system. Rapamycin and everolimus induced apoptosis in PCK cholangiocytes, whereas NVP-BEZ235 inhibited cholangiocyte apoptosis. Notably, the autophagic response was significantly induced following the treatment with NVP-BEZ235, but not rapamycin and everolimus. Inhibition of autophagy using siRNA against protein-light chain3 and 3-methyladenine significantly increased the cell prolifeRative activity of PCK cholangiocytes treated with NVP-BEZ235. In vivo, treatment of the PCK Rat with NVP-BEZ235 attenuated cystic dilatation of the intrahepatic bile ducts, whereas renal cyst development was unaffected. These results suggest that the aberrant activation of the PI3K/mTOR pathway is involved in cystic prolifeRation of cholangiocytes of the PCK Rat, and inhibition of the pathway can reduce cholangiocyte prolifeRation via the mechanism involving apoptosis and/or autophagy.
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Immunohistochemical analysis of the the liver and kidney of the PCK Rat treated with NVP-BEZ235.
2014Co-Authors: Xiang Shan Ren, Yasunori Sato, Shinichi Furubo, Kenichi Harada, Motoko Sasaki, Jing Yu Song, Yasuni NakanumaAbstract:Treatment with NVP-BEZ235 reduced the expression of p-Akt (Ser473), p-mTOR (Ser2448) and p-S6 in bile duct epithelium of the PCK Rat (A). The treatment increased immunohistochemical expression of LC3 in bile duct epithelium of the PCK Rat (B). In the kidney, the expression of p-Akt (Ser473), p-mTOR (Ser2448) and p-S6 was increased in collecting tubule-derived cyst epithelium of the PCK Rat without NVP-BEZ235 treatment compared to those in the renal tubules of normal Rat, and their expression appeared to be reduced in the kidney of the PCK Rat following the treatment (C). Arrows indicate interlobular bile ducts of the normal liver. Original magnifications; x400 (A–C).
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Effects of in-BEZ235 on liver and renal diseases of the PCK Rat.
2014Co-Authors: Xiang Shan Ren, Yasunori Sato, Shinichi Furubo, Kenichi Harada, Motoko Sasaki, Jing Yu Song, Yasuni NakanumaAbstract:Normal and PCK Rats were treated with NVP-BEZ235 or vehicle alone daily between 4 and 8 weeks of age. Liver and kidney sections stained with hematoxylin-eosin showed that NVP-BEZ235 improved dilatation of intrahepatic bile ducts of the PCK Rat, but no beneficial effects were observed on kidney lesions (A). For the PCK Rat, liver and kidney cyst index (B), TUNEL-labeling index of the biliary epithelial cells (C), Ki-67-labeling index of the biliary epithelial cells (D), and liver fibrosis score (E) were determined as described in the Materials and Methods. Treatment with NVP-BEZ235 significantly reduced liver cyst index, TUNEL-labeling index, Ki-67-labeling index and liver fibrosis score of the PCK Rat, whereas kidney cyst index was unaffected. Original magnifications: x200 (A, upper panel; E); x400 (D). Bars, 2 mm (A, lower panel). *, p
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therapeutic approaches for biliary dysgenesis of the PCK Rat an animal model of carolia ââs disease with congenital hepatic fibrosis
Pediatrics & Therapeutics, 2013Co-Authors: Yasunori Sato, Shinichi Furubo, Xiang Shan Ren, Yasuni NakanumaAbstract:The polycystic kidney (PCK) Rat shows multiple segmental and saccular dilatations of the intrahepatic bile ducts associated with portal fibrosis, and is an orthologous rodent model of Caroli?s disease with congenital hepatic fibrosis as well as autosomal recessive polycystic kidney disease. A cholangiocyte cell line that retains properties of the biliary epithelium lining the bile ducts in vivo has been developed from the PCK Rat, and it has provided a novel in vitro system to study the mechanisms of biliary cystogenesis. In particular, the 3-D culture system is useful to explore the effects of therapies on biliary cystogenesis. Studies using the PCK Rat and cultured cholangiocytes have revealed that the biliary dysgenesis is associated with cholangiocyte hyperprolifeRation, cell-matrix interactions and acceleRated fluid transport. The levels of cAMP and intracellular calcium in the cholangiocytes are closely associated with the cyst pathogenesis, and several key signaling pathways such as the activation of B-Raf/MEK/ERK signaling pathway have been identified. This article reviews the advances in therapeutic approaches aiming for amelioRating the hepatobiliary lesions of the PCK Rat, particularly focusing on those for the biliary cystogenesis.
Katherine Macrae Dell - One of the best experts on this subject based on the ideXlab platform.
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Quantitative magnetic resonance imaging assessments of autosomal recessive polycystic kidney disease progression and response to therapy in an animal model.
Pediatric research, 2018Co-Authors: Bernadette O. Erokwu, Christopher A Flask, Christian E. Anderson, Katherine Macrae DellAbstract:Autosomal recessive polycystic kidney disease (ARPKD) is associated with significant mortality and morbidity, and currently, there are no disease-specific treatments available for ARPKD patients. One major limitation in establishing new therapies for ARPKD is a lack of sensitive measures of kidney disease progression. Magnetic resonance imaging (MRI) can provide multiple quantitative assessments of the disease. We applied quantitative image analysis of high-resolution (noncontrast) T2-weighted MRI techniques to study cystic kidney disease progression and response to therapy in the PCK Rat model of ARPKD. Serial imaging over a 2-month period demonstRated that renal cystic burden (RCB, %)=[total cyst volume (TCV)/total kidney volume (TKV) × 100], TCV, and, to a lesser extent, TKV detected cystic kidney disease progression, as well as the therapeutic effect of octreotide, a clinically available medication shown previously to slow both kidney and liver disease progression in this model. All three MRI measures correlated significantly with histologic measures of renal cystic area, although the correlation of RCB and TCV was stronger than that of TKV. These preclinical MRI results provide a basis for applying these quantitative MRI techniques in clinical studies, to stage and measure progression in human ARPKD kidney disease.
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Initial evaluation of hepatic T1 relaxation time as an imaging marker of liver disease associated with autosomal recessive polycystic kidney disease (ARPKD)
NMR in biomedicine, 2015Co-Authors: Ying Gao, Katherine Macrae Dell, Bernadette O. Erokwu, David Desantis, Colleen M. Croniger, Rebecca M. Schur, Jose Mariappuram, Christopher A FlaskAbstract:Autosomal recessive polycystic kidney disease (ARPKD) is a potentially lethal multi-organ disease affecting both the kidneys and the liver. Unfortunately, there are currently no non-invasive methods to monitor liver disease progression in ARPKD patients, limiting the study of potential therapeutic interventions. Herein, we perform an initial investigation of T1 relaxation time as a potential imaging biomarker to quantitatively assess the two primary pathologic hallmarks of ARPKD liver disease: biliary dilatation and periportal fibrosis in the PCK Rat model of ARPKD. T1 relaxation time results were obtained for five PCK Rats at 3 months of age using a Look-Locker acquisition on a Bruker BioSpec 7.0 T MRI scanner. Six three-month-old Sprague-Dawley (SD) Rats were also scanned as controls. All animals were euthanized after the three-month scans for histological and biochemical assessments of bile duct dilatation and hepatic fibrosis for comparison. PCK Rats exhibited significantly increased liver T1 values (mean ± standard deviation = 935 ± 39 ms) compared with age-matched SD control Rats (847 ± 26 ms, p = 0.01). One PCK Rat exhibited severe cholangitis (mean T1 = 1413 ms), which occurs periodically in ARPKD patients. The observed increase in the in vivo liver T1 relaxation time correlated significantly with three histological and biochemical indicators of biliary dilatation and fibrosis: bile duct area percent (R = 0.85, p = 0.002), periportal fibrosis area percent (R = 0.82, p = 0.004), and hydroxyproline content (R = 0.76, p = 0.01). These results suggest that hepatic T1 relaxation time may provide a sensitive and non-invasive imaging biomarker to monitor ARPKD liver disease.
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The renin-angiotensin system and hypertension in autosomal recessive polycystic kidney disease
Pediatric Nephrology, 2010Co-Authors: Miwa Goto, Nita Hoxha, Rania Osman, Katherine Macrae DellAbstract:Hypertension is a well-recognized complication of autosomal recessive polycystic kidney disease (ARPKD). The renin-angiotensin system (RAS) is a key regulator of blood pressure; however, data on the RAS in ARPKD are limited and conflicting, showing both up- and down-regulation. In the current study, we characterized intrarenal and systemic RAS activation in relationship to hypertension and progressive cystic kidney disease in the ARPKD orthologous polycystic kidney (PCK) Rat. Clinical and histological measures of kidney disease, kidney RAS gene expression by quantitative real-time PCR, angiotensin II (Ang II) immunohistochemistry, and systemic Ang I and II levels were assessed in 2-, 4-, and 6-month-old cystic PCK and age-matched normal Rats. PCK Rats developed hypertension and progressive cystic kidney disease without significant worsening of renal function or relative kidney size. Intrarenal renin, ACE and Ang II expression was increased significantly in cystic kidneys; angiotensinogen and Ang II Type I receptor were unchanged. Systemic Ang I and II levels did not differ. This study demonstRates that intrarenal, but not systemic, RAS activation is a prominent feature of ARPKD. These findings help reconcile previous conflicting reports and suggest that intrarenal renin and ACE gene upregulation may represent a novel mechanism for hypertension development or exacerbation in ARPKD.
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Renin-angiotensin system activation in congenital hepatic fibrosis in the PCK Rat model of autosomal recessive polycystic kidney disease.
Journal of pediatric gastroenterology and nutrition, 2010Co-Authors: Miwa Goto, Nita Hoxha, Rania Osman, Jessica Wen, Rebecca G. Wells, Katherine Macrae DellAbstract:Objectives Congenital hepatic fibrosis (CHF) is an important cause of morbidity and mortality in patients with autosomal recessive polycystic kidney disease (ARPKD). The pathogenesis of CHF remains undefined. Several recent studies suggest that the renin-angiotensin system (RAS) is an important mediator of progressive hepatic fibrosis through activation of profibrotic mediators, such as transforming growth factor-beta (TGF-beta). RAS activation has not previously been studied in patients with CHF or in animal models. The aim of the present study was to characterize RAS expression during the course of CHF in the PCK Rat. Materials and methods Studies were conducted in the PCK Rat, an orthologous ARPKD/CHF model, and age-matched normal control Sprague-Dawley Rats. Expression of the RAS components, renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R), as well as the profibrotic mediator TGF-beta, was examined in cystic PCK and control Rat livers at 2, 4, and 6 months of age by quantitative real-time polymerase chain reaction (qRT-PCR). Angiotensin II (ANG II) was examined by immunohistochemistry (IHC). Fibrosis was assessed by IHC using reticulin staining and Masson trichrome. Collagen content was determined by hydroxyproline analysis. Results Progressive fibrosis and increased hepatic collagen content occurred in PCK Rats with age. In 4- and 6-month-old PCK Rat livers, ACE gene expression was markedly increased, 8- and 17-fold, respectively, compared with age-matched control livers. Expression of the other RAS components, renin, angiotensinogen, and AT1R were not significantly different. IHC demonstRated prominent ANG II protein expression in periportal regions in PCK Rats. In contrast, no expression was noted in control livers. TGF-beta expression was also increased in PCK Rat livers with progressive disease. Conclusions The present study demonstRates, for the first time, RAS upregulation in an orthologous Rat ARPKD/CHF model. Increases in ACE and ANG II, as well as the downstream target, the profibrotic mediator TGF-beta, suggest that RAS activation may be an important mediator of CHF disease progression. The findings also suggest that treatment with RAS inhibitors, specifically ACE inhibitors or AT1R blockers, could be therapeutic in slowing disease progression in CHF.
Kim L. R. Brouwer - One of the best experts on this subject based on the ideXlab platform.
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altered expression and function of hepatic transporters in a rodent model of polycystic kidney disease
Drug Metabolism and Disposition, 2019Co-Authors: Jacqueline Bezencon, William J. Brock, James J Beaudoin, Sharin E Roth, Katsuaki Ito, Kim L. R. BrouwerAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is a common form of inherited polycystic kidney disease (PKD) and is a leading cause of kidney failure. Fluid-filled cysts develop in the kidneys of patients with ADPKD, and cysts often form in their liver and other organs. Previous data have shown that bile acids are increased in the liver of polycystic kidney (PCK) Rats, a rodent model of PKD; these changes may be associated with alteRations in liver transporter expression and function. However, the impact of PKD on hepatic transporters has not been characterized. Therefore, this preclinical study was designed to investigate hepatic transporter expression and function in PCK compared with wild-type (WT) Sprague-Dawley Rats. Transporter gene expression was measured by quantitative polymerase chain reaction, and protein levels were quantified by Western blot and liquid chromatography-tandem mass spectroscopy (LC-MS/MS)-based proteomic analysis in Rat livers. Transporter function was assessed in isolated perfused livers (IPLs), and biliary and hepatic total glutathione content was measured. Protein expression of Mrp2 and Oatp1a4 was decreased 3.0-fold and 2.9-fold, respectively, in PCK Rat livers based on Western blot analysis. Proteomic analysis confirmed a decrease in Mrp2 and a decrease in Oatp1a1 expression (PCK/WT Ratios, 0.368 ± 0.098 and 0.563 ± 0.038, respectively; mean ± S.D.). The biliary excretion of 5(6)-carboxy-2',7'-dichlorofluorescein, a substRate of Oatp1a1, Mrp2, and Mrp3, was decreased 28-fold in PCK compared with WT Rat IPLs. Total glutathione was significantly reduced in the bile of PCK Rats. Differences in hepatic transporter expression and function may contribute to altered disposition of Mrp2 and Oatp substRates in PKD.
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altered hepatobiliary disposition of tolvaptan and selected tolvaptan metabolites in a rodent model of polycystic kidney disease
Drug Metabolism and Disposition, 2019Co-Authors: James J Beaudoin, William J. Brock, Jacqueline Bezencon, Yanguang Cao, Katsuhiko Mizuno, Sharin E Roth, Kim L. R. BrouwerAbstract:Tolvaptan, a vasopressin V2-receptor antagonist, has demonstRated efficacy in slowing kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). In the pivotal clinical trial, the incidence of elevated liver enzymes was higher in patients receiving tolvaptan compared with placebo. Adjudication by a panel of expert hepatologists concluded a causal link of tolvaptan to liver injury in patients with ADPKD. An ex situ isolated perfused liver (IPL) study of tolvaptan disposition was undertaken in a rodent model of ADPKD, the polycystic kidney (PCK) Rat (n = 5), and compared with wild-type (WT) Sprague-Dawley Rats (n = 6). Livers were perfused with tolvaptan, followed by a tolvaptan-free washout phase. Total recovery (mean ± S.D. percentage of dose; PCK vs. WT) of tolvaptan and two metabolites, DM-4103 and DM-4107, quantified by liquid chromatography-tandem mass spectroscopy, was 58.14% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% ± <0.01% vs. 0.02% ± 0.01%; P = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% ± 0.57% vs. 0.43% ± 0.29%; P = 0.0017). A pharmacokinetic compartmental model assuming first-order processes was developed to describe the Rate vs. time profiles of tolvaptan and DM-4103 + DM-4107 in Rat IPLs. The model-derived estimate of tolvaptan's biliary clearance was significantly decreased in PCK compared with WT IPLs. The model predicted greater hepatocellular concentRations of tolvaptan and DM-4103 + DM-4107 in PCK compared with WT IPLs. Increased hepatocellular exposure to tolvaptan and metabolites may contribute to the hepatotoxicity in patients with ADPKD treated with tolvaptan.
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altered hepatobiliary disposition of tolvaptan and selected tolvaptan metabolites in a rodent model of polycystic kidney disease
Drug Metabolism and Disposition, 2019Co-Authors: James J Beaudoin, William J. Brock, Jacqueline Bezencon, Katsuhiko Mizuno, Sharin E Roth, Kim L. R. BrouwerAbstract:Tolvaptan, a vasopressin V2-receptor antagonist, has demonstRated efficacy in slowing kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). In the pivotal clinical trial, the incidence of elevated liver enzymes was higher in patients receiving tolvaptan compared with placebo. Adjudication by a panel of expert hepatologists concluded a causal link of tolvaptan to liver injury in patients with ADPKD. An ex situ isolated perfused liver (IPL) study of tolvaptan disposition was undertaken in a rodent model of ADPKD, the polycystic kidney (PCK) Rat (n = 5), and compared with wild-type (WT) Sprague-Dawley Rats (n = 6). Livers were perfused with tolvaptan, followed by a tolvaptan-free washout phase. Total recovery (mean ± S.D. percentage of dose; PCK vs. WT) of tolvaptan and two metabolites, DM-4103 and DM-4107, quantified by liquid chromatography–tandem mass spectroscopy, was 58.14% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (
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Bile Acids as Potential Biomarkers to Assess Liver Impairment in Polycystic Kidney Disease.
International journal of toxicology, 2018Co-Authors: William J. Brock, James J Beaudoin, Sharin E Roth, Jason R. Slizgi, Wei Jia, Kim L. R. BrouwerAbstract:Polycystic kidney disease is characterized by the progressive development of kidney cysts and declining renal function with frequent development of cysts in other organs including the liver. The polycystic kidney (PCK) Rat is a rodent model of polycystic liver disease that has been used to study hepatorenal disease progression and evaluate pharmacotherapeutic interventions. Biomarkers that describe the cyst progression, liver impairment, and/or hepatic cyst burden could provide clinical utility for this disease. In the present study, hepatic cyst volume was measured by magnetic resonance imaging in PCK Rats at 12, 16, and 20 weeks. After 20 weeks, Sprague Dawley (n = 4) and PCK (n = 4) Rats were sacrificed and 42 bile acids were analyzed in the liver, bile, serum, and urine by liquid chromatography coupled to tandem mass spectrometry. Bile acid profiling revealed significant increases in total bile acids (molar sum of all measured bile acids) in the liver (13-fold), serum (6-fold), and urine (3-fold) in PCK Rats, including those speciated bile acids usually associated with hepatotoxicity. Total serum bile acids correlated with markers of liver impairment (liver weight, total liver bile acids, total hepatotoxic liver bile acids, and cyst volume [ r > 0.75; P < 0.05]). Based on these data, serum bile acids may be useful biomarkers of liver impairment in polycystic hepatorenal disease.
Shizuko Nagao - One of the best experts on this subject based on the ideXlab platform.
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Distinct oxylipin alteRations in diverse models of cystic kidney diseases
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2017Co-Authors: Monirujjaman, Masanori Kugita, Tamio Yamaguchi, Shizuko Nagao, Jessay G. Devassy, Melissa Gabbs, Amir Ravandi, Nikhil Sidhu, Jing Zhou, Harold M AukemaAbstract:Abstract Cystic kidney diseases are characterized by multiple renal cysts and are the leading cause of inherited renal disease. Oxylipins are bioactive lipids derived from fatty acids formed via cyclooxygenase, lipoxygenase and cytochrome P450 activity, and are important regulators of renal health and disease. Oxylipins are altered in nephronophthisis, a type of cystic kidney disease. To further investigate and to determine whether other cystic renal diseases share these abnormalities, a targeted lipidomic analysis of renal oxylipins was performed in orthologous models of autosomal dominant polycystic kidney disease 1 (Mx1Cre+ Pkd1flox/flox mouse) and 2 (Pkd2ws25/− mouse), autosomal recessive polycystic kidney disease (PCK Rat) and nephronophthisis (jck/jck mouse). Kidney cyclooxygenase oxylipins were consistently higher in all diseased kidneys, even in very early stage disease. On the other hand, cytochrome P450 epoxygenase derived oxylipins were lower only in the autosomal recessive polycystic kidney disease and nephronophthisis models, while lipoxygenase and cytochrome P450 hydroxylase derived oxylipins were lower only in nephronophthisis. Sex effects on renal oxylipin alteRations were observed but they did not always coincide with sex effects on disease. For oxylipins with sex effects, arachidonic acid derived oxylipins formed via cyclooxygenases and lipoxygenases were higher in females, while oxylipins from other fatty acids and via cytochrome P450 enzymes were higher in males. The consistent and unique patterns of oxylipin alteRations in the different models indicates the importance of these bioactive lipids in cystic renal diseases, suggesting that pharmacological agents (e.g. cyclooxygenase inhibitors) may be useful in treating these disorders, for which effective treatment remains elusive.
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Telmisartan AmelioRates Fibrocystic Liver Disease in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney
2016Co-Authors: Daisuke Yoshihara, Masanori Kugita, Tamio Yamaguchi, Mai Sasaki, Shigeo Horie, Koichi Nakanishi, Harold M Aukema, Takaaki Abe, Shizuko NagaoAbstract:Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK Rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular prolifeRation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome prolifeRator activated receptor (PPAR)-c full agonist amelioRated kidney and liver disease in PCK Rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-c agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan amelioRates progression of polycystic kidney and fibrocystic liver disease in PCK Rats. Five male and 5 female PCK and normal control (+/ +) Rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ Rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-b, and th
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telmisartan amelioRates fibrocystic liver disease in an orthologous Rat model of human autosomal recessive polycystic kidney disease
PLOS ONE, 2013Co-Authors: Daisuke Yoshihara, Masanori Kugita, Tamio Yamaguchi, Mai Sasaki, Shigeo Horie, Koichi Nakanishi, Harold M Aukema, Shizuko NagaoAbstract:Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK Rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular prolifeRation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome prolifeRator activated receptor (PPAR)-γ full agonist amelioRated kidney and liver disease in PCK Rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan amelioRates progression of polycystic kidney and fibrocystic liver disease in PCK Rats. Five male and 5 female PCK and normal control (+/+) Rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ Rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK Rats. Therefore, telmisartan amelioRates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular prolifeRation and interstitial fibrosis in PCK Rats. The present results support the potential therapeutic use of ARBs for the treatment of fibrocystic liver disease in ARPKD patients.
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Structure and function of the pancreas in the polycystic kidney Rat
Pancreas, 2012Co-Authors: Satoru Naruse, Shizuko Nagao, Daisuke Yoshihara, Sonoko Furuya, Akiko Yamamoto, Miyuki Nakakuki, Mu-xin Wei, Takaharu KondoAbstract:OBJECTIVES Mutation in the Pkhd1 gene that encodes a ciliary protein, fibrocystin, causes multiple cysts in the kidneys and liver in the polycystic kidney (PCK) Rat, a model for human autosomal recessive PCK disease. To clarify the role of primary cilia in the pancreatic duct, we examined the structure and function of the exocrine pancreas of PCK Rats. METHODS Pancreatic juice and bile were collected from anesthetized Rats. Pancreatic ductal structure was analyzed by microdissection and immunohist0chemistry. RESULTS Histologically pancreatic acini were apparently normal, and no cysts were detected in the pancreas. Larger pancreatic ducts were irregularly dilated with enhanced expression of AQP1 in epithelial cells. The pancreatic duct of PCK Rats exhibited significantly (P < 0.05) higher distensibility than that of wild-type (WT) Rat at a physiological luminal pressure (3 cm H2O). Pancreatic fluid secretion stimulated with a physiological dose of secretin (0.03 nmol/kg per hour) in PCK Rats was significantly smaller than that in WT, but the differences were not significant at higher doses. The amylase responses to carbamylcholine were not different between PCK and WT Rats. CONCLUSIONS These findings suggest that fibrocystin/primary cilia-dependent mechanisms may play a role in the regulation of pancreatic ductal structure and fluid secretion.
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Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK Rat model of autosomal-recessive polycystic kidney disease
American Journal of Physiology-renal Physiology, 2010Co-Authors: Hiroko Togawa, Koichi Nakanishi, Kazuhiro Nishii, Hironobu Mukaiyama, Taketsugu Hama, Yuko Shima, Mayumi Sako, Masayasu Miyajima, Kandai Nozu, Shizuko NagaoAbstract:In polycystic kidney disease (PKD), cyst lining cells show polarity abnormalities. Recent studies have demonstRated loss of cell contact in cyst cells, suggesting induction of epithelial-to-mesench...