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HIF in renal disease

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https://www.readbyqxmd.com/read/29363499/metabolic-profiling-of-the-novel-hif2%C3%AE-inhibitor-pt2385-in-vivo-and-in-vitro
#1
Cen Xie, Xiaoxia Gao, Dongxu Sun, Youbo Zhang, Kristopher W Krausz, Xuemei Qin, Frank Gonzalez
PT2385 is a first-in-class, selective small molecule inhibitor of hypoxia inducible factor-2α (HIF-2α) developed for the treatment of advanced clear cell renal cell carcinoma. Preclinical results demonstrated that PT2385 has potent anti-tumor efficacy in mouse xenograft models of kidney cancer. It also has activity toward metabolic disease in a mouse model. However, no metabolism data is currently publicly available. It is of great importance to characterize the metabolism of PT2385 and identify its effect on systemic homeostasis in mice...
January 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29344375/elevated-serum-levels-of-cardiovascular-biomarkers-are-associated-with-progression-of-renal-cancer
#2
Takao Kamai, Yuumi Tokura, Toshitaka Uematsu, Kazumasa Sakamoto, Issei Suzuki, Kohei Takei, Takahiro Narimatsu, Tsunehito Kambara, Hideo Yuki, Hironori Betsunoh, Hideyuki Abe, Yoshitatsu Fukabori, Masahiro Yashi, Ken-Ichiro Yoshida
Objective: Renal cell carcinoma (RCC) is a hypervascular tumour due to high constitutive production of vascular endothelial growth factor (VEGF), which is activated by hypoxia-inducible factor (HIF). Elevated levels of cardiovascular peptides, including brain natriuretic peptide (BNP), have been reported in patients with cancer, regardless of whether they have overt cardiovascular disease. Furthermore, it has been demonstrated that hypoxia stimulates BNP production by an HIF-dependent manner...
2018: Open Heart
https://www.readbyqxmd.com/read/29328439/prognostic-significance-of-hypoxia-inducible-factor-1%C3%AE-expression-in-patients-with-clear-cell-renal-cell-carcinoma
#3
Shuiqing Wu, Fen Jiang, Hongtao Wu, Yinhuai Wang, Ran Xu, Jian Cao, Qiong Lu, Xuan Zhu, Zhaohui Zhong, Xiaokun Zhao
The prognostic significance of hypoxia inducible factor-1α (HIF-1α) expression in tumors and the levels of preoperative hemoglobin in clear cell renal cell carcinoma (ccRCC), with or without concomitant chronic obstructive pulmonary disease (COPD), was investigated. A total of 128 patients with ccRCC who underwent surgery were analyzed using retrospective methods. Overall survival (OS) and progression free survival (PFS) were analyzed with clinicopathological variables, including preoperative hemoglobin levels, COPD and the levels of HIF‑1α expression, by Kaplan‑Meier survival analysis...
January 9, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29299781/slit2-robo1-signaling-is-involved-in-angiogenesis-of-glomerular-endothelial-cells-exposed-to-a-diabetic-like-environment
#4
Junhui Liu, Weiping Hou, Tao Guan, Luyao Tang, Xufei Zhu, Yi Li, Shihui Hou, Jun Zhang, Hua Chen, Yunjian Huang
Abnormal angiogenesis plays a pathological role in diabetic nephropathy (DN), contributing to glomerular hypertrophy and microalbuminuria. Slit2/Robo1 signaling participates in angiogenesis in some pathological contexts, but whether it is involved in glomerular abnormal angiogenesis of early DN is unclear. The present study evaluated the effects of Slit2/Robo1 signaling pathway on angiogenesis of human renal glomerular endothelial cells (HRGECs) exposed to a diabetic-like environment or recombinant Slit2-N...
January 3, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29261470/science-to-practice-can-functional-mr-imaging-be-useful-in-the-evaluation-of-cardiorenal-syndrome
#5
Amit Pursnani, Pottumarthi V Prasad
Functional magnetic resonance (MR) imaging of the kidneys has gained interest recently, especially in the detection of early changes in acute kidney injury or to predict progression of chronic kidney disease (CKD). The application of these methods to cardiorenal syndrome (CRS) is novel. CRS is widely accepted as a complex clinical problem routinely faced by clinicians. In this issue, Chang et al ( 1 ) present their preliminary experience applying blood oxygen level-dependent (BOLD) MR imaging to the kidneys in mice with experimental myocardial infarction...
January 2018: Radiology
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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