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HIF in renal disease

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https://www.readbyqxmd.com/read/29206844/restoration-of-the-prolyl-hydroxylase-domain-protein-3-oxygen-sensing-mechanism-is-responsible-for-regulation-of-hif2%C3%AE-expression-and-induction-of-sensitivity-of-myeloma-cells-to-hypoxia-mediated-apoptosis
#1
Gilberto Gastelum, Aleksandra Poteshkina, Mysore Veena, Edgar Artiga, Geraldine Weckstein, Patrick Frost
Multiple myeloma (MM) is an incurable disease of malignant plasma B-cells that infiltrate the bone marrow (BM), resulting in bone destruction, anemia, renal impairment and infections. Physiologically, the BM microenvironment is hypoxic and this promotes MM progression and contributes to resistance to chemotherapy. Since aberrant hypoxic responses may result in the selection of more aggressive tumor phenotypes, we hypothesized that targeting the hypoxia-inducible factor (HIF) pathways will be an effective anti-MM therapeutic strategy...
2017: PloS One
https://www.readbyqxmd.com/read/29172268/effect-of-targeted-therapy-with-pazopanib-on-expression-levels-of-transcription-growth-factors-and-components-of-akt-m-tor-signaling-pathway-in-patients-with-renal-cell-carcinoma
#2
Liudmila V Spirina, Evgeny A Usynin, Zahar A Yurmazov, Elena M Slonimskaya, Irina V Kondakova
Background: The effect of the targeted therapy on cancer molecular markers remains currently unknown. The aim of the study was to investigate the expression and content of transcription, growth factors and components of the AKT/m-TOR signaling pathway in kidney cancer patients before and after targeted therapy with pazopanib. Methods: A total of 157 patients with renal cell carcinoma were enrolled into the study. The level of mRNA expression was investigated by real-time PCR, and the contents of transcription and growth factors, as well as the levels of AKT/m- TOR signaling pathway components were determined by ELISA and Western blotting...
November 26, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/29158549/hypoxia-inducible-factor-1%C3%AE-mediates-the-profibrotic-effect-of-albumin-in-renal-tubular-cells
#3
Junping Hu, Weili Wang, Fan Zhang, Pin-Lan Li, Krishna M Boini, Fan Yi, Ningjun Li
Proteinuria is closely associated with the progression of chronic kidney diseases (CKD) by producing renal tubulointerstitial fibrosis. Over-activation of hypoxia inducible factor (HIF)-1α has been implicated in the progression of CKD. The present study tested the hypothesis that HIF-1α mediates albumin-induced profibrotic effect in cultured renal proximal tubular cells. Incubation of the cells with albumin (40 μg/ml) for 72 hrs significantly increased the protein levels of HIF-1α, tissue inhibitor of metalloproteinase (TIMP)-1 and collagen-I, which were blocked by HIF-1α shRNA...
November 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#4
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
November 16, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29113209/prognostic-value-of-copper-transporter-1-expression-in-patients-with-clear-cell-renal-cell-carcinoma
#5
Yu Xia, Li Liu, Qi Bai, Qilai Long, Jiajun Wang, Wei Xi, Jiejie Xu, Jianming Guo
Clear cell renal cell carcinoma (ccRCC) features a Von Hippel-Lindau mutation, associated with a hypoxia-inducible factor (HIF) imbalance. Copper transporter 1 (CTR1) may also promote tumor progression through the modulation of the HIF pathway by copper. Therefore, the present study explored the prognostic effect of tumor CTR1 expression in patients with ccRCC. A total of 293 patients with ccRCC that underwent nephrectomy were retrospectively enrolled. CTR1 expression was assessed by immunohistochemistry, and its association with clinicopathological features and prognosis were evaluated...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29074377/dual-therapeutic-effects-of-an-albumin-based-nitric-oxide-donor-on-two-experimental-models-of-chronic-kidney-disease
#6
Shun Oshiro, Yu Ishima, Maeda Hitoshi, Naoko Honda, Bi Jing, Ryo Kinoshita, Mayumi Ikeda, Yasunori Iwao, Tadashi Imafuku, Kento Nishida, Sigeyuki Miyamura, Hiroshi Watanabe, Masaki Otagiri, Toru Maruyama
Chronic kidney disease (CKD) is accompanied by a variety of complications, typically renal anemia and kidney fibrosis. Accordingly, it is desirable to develop the novel therapeutics that can treat these CKD conditions. Since nitric oxide (NO) has multiple functions including hypoxia inducible factor (HIF) stabilizing, anti-inflammatory, anti-oxidative and anti-apoptoic activities, the use of NO for the CKD therapy has attracted considerable interest. Here, we evaluate the therapeutic impacts of S-nitrosated human serum albumin (SNO-HSA), a long-lasting NO donor, on two animal models of CKD...
October 23, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29073196/fgf23-expression-in-rodents-is-directly-induced-via-erythropoietin-after-inhibition-of-hypoxia-inducible-factor-proline-hydroxylase
#7
Ingo Flamme, Peter Ellinghaus, Diana Urrego, Thilo Krüger
Plasma levels of FGF23 are increased in patients with chronic kidney disease. Beside its role in phosphate homeostasis, iron deficiency and anemia are associated with increased FGF23 plasma levels. Recently, FGF23 plasma levels were shown to be increased in mice after treatment with hypoxia inducible factor-proline hydroxylase (HIF-PH) inhibitors which are strong inducers of erythropoietin and erythropoiesis and are known to modulate iron uptake and availability. Therefore we investigated a potential context between expression of FGF23 and stimulation of erythropoiesis using a HIF-PH inhibitor and erythropoietin in rats...
2017: PloS One
https://www.readbyqxmd.com/read/29033582/hif-pathway-and-c-myc-as-biomarkers-for-response-to-sunitinib-in-metastatic-clear-cell-renal-cell-carcinoma
#8
P Maroto, E Esteban, E Fernández Parra, M J Mendez-Vidal, M Domenech, B Pérez-Valderrama, V Calderero, J L Pérez-Gracia, E Grande, F Algaba
BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is a heterogeneous disease with a different clinical behavior and response to targeted therapies. Differences in hypoxia-inducible factor (HIF) expression have been used to classify von Hippel-Lindau gene (VHL)-deficient ccRCC tumors. c-Myc may be driving proliferation in HIF-2α-expressing tumors in a growth factor-independent manner. OBJECTIVE: To explore the HIF-1α, HIF-2α and c-Myc baseline expression as potential predictors of sunitinib outcome as well as the effectiveness and safety with sunitinib in patients with metastatic ccRCC in routine clinical practice...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28978825/pathogenesis-and-treatment-of-anemia-in-chronic-kidney-disease
#9
Masaomi Nangaku
Chronic kidney disease leads to dysfunction of renal erythropoietin-producing cells, resulting in a decrease in erythrocyte production. A decrease in oxygen delivery to vital organs due to anemia results in worse quality of life and is associated with poor prognosis of the patients. Treatment with human recombinant erythropoietin or its improved version of erythropoiesis-stimulating agent (ESA) with a longer half-life is effective. However, some patients show hyporesponsiveness to ESA. Hyporesponsiveness to ESA, which can be induced by factors such as inflammation and uremic toxins, is associated with poor prognosis...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28963640/development-of-response-classifier-for-vascular-endothelial-growth-factor-receptor-vegfr-tyrosine-kinase-inhibitor-tki-in-metastatic-renal-cell-carcinoma
#10
Heounjeong Go, Mun Jung Kang, Pil-Jong Kim, Jae-Lyun Lee, Ji Y Park, Ja-Min Park, Jae Y Ro, Yong Mee Cho
Vascular endothelial growth factor receptor (VEGFR)-targeted therapy improved the outcome of metastatic renal cell carcinoma (mRCC) patients. However, a prediction of the response to VEGFR-tyrosine kinase inhibitor (TKI) remains to be elucidated. We aimed to develop a classifier for VEGFR-TKI responsiveness in mRCC patients. Among 101 mRCC patients, ones with complete response, partial response, or ≥24 weeks stable disease in response to VEGFR-TKI treatment were defined as clinical benefit group, whereas patients with <24 weeks stable disease or progressive disease were classified as clinical non-benefit group...
September 29, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28950297/a-randomized-phase-ii-trial-of-crlx101-in-combination-with-bevacizumab-versus-standard-of-care-in-patients-with-advanced-renal-cell-carcinoma
#11
M H Voss, A Hussain, N Vogelzang, J L Lee, B Keam, S Y Rha, U Vaishampayan, W B Harris, S Richey, J M Randall, D Shaffer, A Cohn, T Crowell, J Li, A Senderowicz, E Stone, R Figlin, R J Motzer, N B Haas, T Hutson
Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28925400/the-hif-and-other-quandaries-in-vhl-disease
#12
REVIEW
D Tarade, M Ohh
Mutations in VHL underlie von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome with several subtypes depending on the risk of developing certain combination of classic features, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma and pheochromocytoma. Although numerous potential substrates and functions of pVHL have been described over the past decade, the best-defined role of pVHL has remained as the negative regulator of the heterodimeric hypoxia-inducible factor (HIF) transcription factor via the oxygen-dependent ubiquitin-mediated degradation of HIF-α subunit...
September 18, 2017: Oncogene
https://www.readbyqxmd.com/read/28900259/selective-tubular-activation-of-hypoxia-inducible-factor-2%C3%AE-has-dual-effects-on-renal-fibrosis
#13
Kyoung Hye Kong, Hyung Jung Oh, Beom Jin Lim, Minsuk Kim, Ki-Hwan Han, Youn-Hee Choi, Kihwan Kwon, Bo Young Nam, Kyoung Sook Park, Jung Tak Park, Seung Hyeok Han, Tae-Hyun Yoo, Shina Lee, Seung-Jung Kim, Duk-Hee Kang, Kyu Bok Choi, Vera Eremina, Susan E Quaggin, Dong-Ryeol Ryu, Shin-Wook Kang
Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28857467/impaired-erythropoietin-synthesis-in-chronic-kidney-disease-is-caused-by-alterations-in-extracellular-matrix-composition
#14
Gemma Olmos, José M Muñoz-Félix, Inés Mora, Anton Gerhard Müller, Maria Piedad Ruiz-Torres, José M López-Novoa, Diego Rodríguez-Puyol
Renal fibrosis and anaemia are two of the most relevant events in chronic kidney disease. Fibrosis is characterized by the accumulation of extracellular matrix proteins in the glomeruli and tubular interstitium. Anaemia is the consequence of a decrease in erythropoietin production in fibrotic kidneys. This work analyses the possibility that the accumulation of abnormal collagens in kidney interstitium could be one of the mechanisms responsible for erythropoietin decreased synthesis. In renal interstitial fibroblast grown on collagen I, erythropoietin mRNA expression and HIF-2α protein decreased, whereas focal adhesion kinase protein (FAK) phosphorylation and proteasome activity increased, compared to cells grown on collagen IV...
August 30, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28819298/transcriptome-based-network-analysis-reveals-renal-cell-type-specific-dysregulation-of-hypoxia-associated-transcripts
#15
Natallia Shved, Gregor Warsow, Felix Eichinger, David Hoogewijs, Simone Brandt, Peter Wild, Matthias Kretzler, Clemens D Cohen, Maja T Lindenmeyer
Accumulating evidence suggests that dysregulation of hypoxia-regulated transcriptional mechanisms is involved in development of chronic kidney diseases (CKD). However, it remains unclear how hypoxia-induced transcription factors (HIFs) and subsequent biological processes contribute to CKD development and progression. In our study, genome-wide expression profiles of more than 200 renal biopsies from patients with different CKD stages revealed significant correlation of HIF-target genes with eGFR in glomeruli and tubulointerstitium...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28812986/epigenome-aberrations-emerging-driving-factors-of-the-clear-cell-renal-cell-carcinoma
#16
REVIEW
Ali Mehdi, Yasser Riazalhosseini
Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC...
August 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28753789/integrated-phenotypic-genotypic-analysis-of-papillary-renal-cell-carcinoma-subtypes-identification-of-prognostic-markers-cancer-related-pathways-and-implications-for-therapy
#17
Rola M Saleeb, Pamela Plant, Eriny Tawedrous, Adriana Krizova, Fadi Brimo, Andrew J Evans, Samantha Jane Wala, John Bartlett, Qiang Ding, Dina Boles, Fabio Rotando, Mina Farag, George M Yousef
BACKGROUND: Two histologic subtypes are recognized for papillary renal cell carcinoma (PRCC). Studies have shown that the subtypes differ in characteristic genetic alterations and clinical behavior. Clinically, the subtypes are managed similarly. OBJECTIVES: To analyze the biological differences between the two PRCC histological subtypes, in order to further guide their clinical management. DESIGN, SETTING, AND PARTICIPANTS: PRCC cohort consisting of 317 patients from the Cancer Genome Atlas database and our institution...
September 22, 2016: European Urology Focus
https://www.readbyqxmd.com/read/28701475/hif-activation-causes-synthetic-lethality-between-the-vhl-tumor-suppressor-and-the-ezh1-histone-methyltransferase
#18
Abhishek A Chakraborty, Eijiro Nakamura, Jun Qi, Amanda Creech, Jacob D Jaffe, Joshiawa Paulk, Jesse S Novak, Kshithija Nagulapalli, Samuel K McBrayer, Glenn S Cowley, Javier Pineda, Jiaxi Song, Yaoyu E Wang, Steven A Carr, David E Root, Sabina Signoretti, James E Bradner, William G Kaelin
Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). pVHL loss causes the transcriptional activation of hypoxia-inducible factor (HIF) target genes, including many genes that encode histone lysine demethylases. Moreover, chromatin regulators are frequently mutated in this disease. We found that ccRCC displays increased H3K27 acetylation and a shift toward mono- or unmethylated H3K27 caused by an HIF-dependent increase in H3K27 demethylase activity...
July 12, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28686686/protective-effect-of-zinc-preconditioning-against-renal-ischemia-reperfusion-injury-is-dose-dependent
#19
Kenny Rao, Kapil Sethi, Joseph Ischia, Luke Gibson, Laurence Galea, Lin Xiao, Mildred Yim, Mike Chang, Nathan Papa, Damien Bolton, Arthur Shulkes, Graham S Baldwin, Oneel Patel
OBJECTIVES: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and chronic kidney disease. Two promising preconditioning methods for the kidney, intermittent arterial clamping (IC) and treatment with the hypoxia mimetic cobalt chloride, have never been directly compared. Furthermore, the protective efficacy of the chemically related transition metal Zn2+ against renal IRI is unclear. Although Co2+ ions have been shown to protect the kidney via hypoxia inducible factor (HIF), the effect of Zn2+ ions on the induction of HIF1α, HIF2α and HIF3α has not been investigated previously...
2017: PloS One
https://www.readbyqxmd.com/read/28627412/macrophages-regulate-unilateral-ureteral-obstruction-induced-renal-lymphangiogenesis-through-c-c-motif-chemokine-receptor-2-dependent-phosphatidylinositol-3-kinase-akt-mechanistic-target-of%C3%A2-rapamycin-signaling-and-hypoxia-inducible-factor-1%C3%AE-vascular-endothelial
#20
Yan-Chao Guo, Meng Zhang, Fa-Xi Wang, Guang-Chang Pei, Fei Sun, Ying Zhang, Xiaoyu He, Yi Wang, Jia Song, Feng-Ming Zhu, Nuruliarizki S Pandupuspitasari, Jing Liu, Kun Huang, Ping Yang, Fei Xiong, Shu Zhang, Qilin Yu, Ying Yao, Cong-Yi Wang
Lymphangiogenesis occurs during renal fibrosis in patients with chronic kidney diseases and vascular endothelial growth factor (VEGF)-C is required for the formation of lymphatic vessels; however, the underlying mechanisms remain unclear. We demonstrate that macrophages can regulate unilateral ureteral obstruction (UUO)-induced renal lymphangiogenesis by expressing high levels of VEGF-C by C-C motif chemokine receptor 2 (CCR2)-mediated signaling. Mice deficient in Ccr2 manifested repressed lymphangiogenesis along with attenuated renal injury and fibrosis after UUO induction...
August 2017: American Journal of Pathology
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