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HIF in renal disease

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https://www.readbyqxmd.com/read/29033582/hif-pathway-and-c-myc-as-biomarkers-for-response-to-sunitinib-in-metastatic-clear-cell-renal-cell-carcinoma
#1
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
#2
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
#3
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-2-trial-of-crlx101-in-combination-with-bevacizumab-versus-standard-of-care-in-patients-with-advanced-renal-cell-carcinoma
#4
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 (NDC) enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel NDC containing camptothecin a potent inhibitor of topoisomerase I and the hypoxia-inducible factors (HIF) 1α and 2α. In a phase 1b/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase 2 trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC...
September 11, 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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/28624320/prognostic-value-of-the-vhl-hif-1%C3%AE-and-vegf-signaling-pathway-and-associated-mapk-erk1-2-and-erk5-pathways-in-clear-cell-renal-cell-carcinoma-a-long-term-study
#14
Antonio S Salinas-Sánchez, Leticia Serrano-Oviedo, Syongh Y Nam-Cha, Olga Roche-Losada, Ricardo Sánchez-Prieto, José M Giménez-Bachs
BACKGROUND: The prognostic value of molecular markers in renal cell carcinoma has been investigated in several studies. Although their value is still not confirmed, various proteins are important. We describe the effect on long-term survival of the status of the von Hippel-Lindau (VHL) hypoxia-inducible factor 1-α (HIF1-α) signaling pathway as well as associated mitogen-activated protein kinase (extracellular signal-regulated kinase [ERK]1/2 and ERK5). PATIENTS AND METHODS: A prospective, longitudinal cohort study was conducted with 50 patients diagnosed with clear-cell renal cell carcinoma to analyze VHL mutations and hypermethylation as well as VHL, HIF1-α, vascular endothelial growth factor (VEGF), ERK1/2, and ERK5 protein expression...
May 25, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28606929/targeting-oxygen-sensing-prolyl-hydroxylase-for-metformin-associated-lactic-acidosis-treatment
#15
Tomoko Oyaizu-Toramaru, Tomohiro Suhara, Noriyo Hayakawa, Takashi Nakamura, Akiko Kubo, Shizuka Minamishima, Kyoji Yamaguchi, Takako Hishiki, Hiroshi Morisaki, Makoto Suematsu, Yoji Andrew Minamishima
Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxia-inducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels...
August 15, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28577740/oxygen-sensors-as-therapeutic-targets-in-kidney-disease
#16
Volker H Haase
Hypoxia is a common clinical problem that has profound effects on renal homeostasis. Prolyl-4-hydroxylases PHD1, 2 and 3 function as oxygen sensors and control the activity of hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor that regulates a multitude of hypoxia responses, which help cells and tissues to adapt to low oxygen environments. This review provides an overview of the molecular mechanisms that govern these hypoxia responses and discusses clinical experience with compounds that inhibit prolyl-4-hydroxylases to harness HIF responses for therapy in nephrology...
April 2017: Néphrologie & Thérapeutique
https://www.readbyqxmd.com/read/28553932/combined-mutation-in-vhl-trp53-and-rb1-causes-clear-cell-renal-cell-carcinoma-in-mice
#17
Sabine Harlander, Désirée Schönenberger, Nora C Toussaint, Michael Prummer, Antonella Catalano, Laura Brandt, Holger Moch, Peter J Wild, Ian J Frew
Clear cell renal cell carcinomas (ccRCCs) frequently exhibit inactivation of the von Hippel-Lindau tumor-suppressor gene, VHL, and often harbor multiple copy-number alterations in genes that regulate cell cycle progression. We show here that modeling these genetic alterations by combined deletion of Vhl, Trp53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC. These tumors arose from proximal tubule epithelial cells and shared molecular markers and mRNA expression profiles with human ccRCC...
July 2017: Nature Medicine
https://www.readbyqxmd.com/read/28538016/hypoxia-inducible-factor-activation-in-diabetic-kidney-disease
#18
Patrik Persson, Fredrik Palm
PURPOSE OF REVIEW: Tissue hypoxia is present in kidneys from diabetic patients and constitutes a central pathway to diabetic kidney disease (DKD). This review summarizes regulation of hypoxia inducible factor (HIF) and interventions towards the same for treatment of DKD. RECENT FINDINGS: In the hypoxic diabetic kidney, HIF activity and the effects of HIF signaling seem to be cell-specific. In mesangial cells, elevated glucose levels induce HIF activity by a hypoxia-independent mechanism...
September 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/28492542/lncrna-hotair-regulates-hif-1%C3%AE-axl-signaling-through-inhibition-of-mir-217-in-renal-cell-carcinoma
#19
Quan Hong, Ou Li, Wei Zheng, Wen-Zhen Xiao, Lu Zhang, Di Wu, Guang-Yan Cai, John Cijiang He, Xiang-Mei Chen
Long non-coding RNA HOTAIR was regarded as an oncogene in multiple cancers. Previous studies have shown that HOTAIR is involved in the proliferation and tumorigenesis of renal carcinoma cells, while microRNA (miR)-217 functions as a tumor suppressor in renal cell carcinoma (Rcc). However, the underlying molecular mechanism of HOTAIR in Rcc, especially in association with miR-217, has not been studied. In this study, we first demonstrated that HOTAIR expression was upregulated, which was correlated with tumor progression, and miR-217 downregulated in Rcc tissues and cells...
May 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28483447/therapeutic-targeting-of-the-hif-oxygen-sensing-pathway-lessons-learned-from-clinical-studies
#20
REVIEW
Volker H Haase
The oxygen-sensitive hypoxia-inducible factor (HIF) pathway plays a central role in the control of erythropoiesis and iron metabolism. The discovery of prolyl hydroxylase domain (PHD) proteins as key regulators of HIF activity has led to the development of inhibitory compounds that are now in phase 3 clinical development for the treatment of renal anemia, a condition that is commonly found in patients with advanced chronic kidney disease. This review provides a concise overview of clinical effects associated with pharmacologic PHD inhibition and was written in memory of Professor Lorenz Poellinger...
July 15, 2017: Experimental Cell Research
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