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HIF in renal disease

Baijun Dong, Yujing Gao, Xunlei Kang, Hongchang Gao, Jin Zhang, Hua Guo, Mingjian J You, Wei Xue, Jinke Cheng, Yiran Huang
Metabolic shift toward aerobic glycolysis is a fundamental element contributing to the development and progression of clear cell renal cell carcinoma (ccRCC). We and others previously observed enhanced glycolysis and diminished tricarboxylic acid (TCA) cycle activity in ccRCC tissue. Here, by integrated gene expression and metabolomic analyses of 36 matched pairs of tumor and adjacent normal tissues, we showed that expression of Sentrin/SUMO-specific protease 1 (SENP1) is positively associated with glycolysis levels in ccRCC...
October 12, 2016: Oncotarget
Hannah L Bader, Tien Hsu
BACKGROUND: Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome-VHL disease-and are also frequently observed in sporadic renal cell carcinoma of the clear cell type (ccRCC). VHL disease is characterized by malignant and benign tumors in a few specific tissues, including ccRCC, hemangioblastoma and pheochromocytoma. The etiology of these tumors remains unresolved. METHODS: Conditional inactivation of the VHL gene in mouse (Vhlh) was generated to examine the pathophysiological role of the VHL gene function...
October 12, 2016: BMC Cancer
Yuh-Feng Lin, I-Jen Chiu, Fong-Yu Cheng, Yu-Hsuan Lee, Ying-Jan Wang, Yung-Ho Hsu, Hui-Wen Chiu
BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are used in an increasing number of products, including rubber manufacture, cosmetics, pigments, food additives, medicine, chemical fibers and electronics. However, the molecular mechanisms underlying ZnO NP nephrotoxicity remain unclear. In this study, we evaluated the potential toxicity of ZnO NPs in kidney cells in vitro and in vivo. RESULTS: We found that ZnO NPs were apparently engulfed by the HEK-293 human embryonic kidney cells and then induced reactive oxygen species (ROS) generation...
September 27, 2016: Particle and Fibre Toxicology
Wenfang Chen, Haley Hill, Alana Christie, Min Soo Kim, Eboni Holloman, Andrea Pavia-Jimenez, Farrah Homayoun, Yuanqing Ma, Nirav Patel, Paul Yell, Guiyang Hao, Qurratulain Yousuf, Allison Joyce, Ivan Pedrosa, Heather Geiger, He Zhang, Jenny Chang, Kevin H Gardner, Richard K Bruick, Catherine Reeves, Tae Hyun Hwang, Kevin Courtney, Eugene Frenkel, Xiankai Sun, Naseem Zojwalla, Tai Wong, James P Rizzi, Eli M Wallace, John A Josey, Yang Xie, Xian-Jin Xie, Payal Kapur, Renée M McKay, James Brugarolas
Clear cell Renal Cell Carcinoma (ccRCC) is characterized by VHL inactivation(1,2). Because no other gene is mutated as frequently, and VHL mutations are truncal(3), VHL inactivation is regarded as the governing event(4). VHL loss activates HIF-2, and constitutive HIF-2 restores tumorigenesis in VHL-reconstituted ccRCC cells(5). HIF-2 is implicated in angiogenesis and multiple other processes(6,7,8,9), but angiogenesis is the main target of drugs like sunitinib(10). HIF-2, a transcription factor, has been regarded as undruggable(11)...
September 5, 2016: Nature
Andre Kraus, Steffen Grampp, Margarete Goppelt-Struebe, Rainer Schreiber, Karl Kunzelmann, Dorien J M Peters, Jens Leipziger, Gunnar Schley, Johannes Schödel, Kai-Uwe Eckardt, Bjoern Buchholz
Polycystic kidney diseases are characterized by numerous renal cysts that continuously enlarge resulting in compression of intact nephrons and tissue hypoxia. Recently, we have shown that hypoxia-inducible factor (HIF)-1α promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calcium-activated chloride secretion. Here, we report that HIF-1α directly activates expression of the purinergic receptor P2Y2R in human primary renal tubular cells. In addition, we found that P2Y2R is highly expressed in cyst-lining cells of human ADPKD kidneys as well as PKD1 orthologous mouse kidneys...
August 26, 2016: Purinergic Signalling
Jolanta Malyszko, Jacek S Malyszko
INTRODUCTION: Anemia has been remained one of the most characteristic and visible manifestations of chronic renal failure. Correction of anemia requires two main treatment strategies: increased stimulation of erythropoiesis, and maintenance of an adequate iron supply to the bone marrow. AREAS COVERED: Erythropoiesis activating agents became a mainstay in the treatment of renal anemia for more than 25 years. Recently, there have been several attempts to introduce new drugs to stimulate erythropoiesis or affect the hepcidin-ferroportin pathway...
September 2016: Expert Opinion on Emerging Drugs
Bethany Baumann, Tomoko Hayashida, Xiaoyan Liang, H William Schnaper
The function of hypoxia-inducible factor-1α (HIF-1α) in chronic kidney disease is disputed. Here we report that interactions of HIF-1α with transforming growth factor-β (TGF-β) signaling may promote its fibrotic effects. Knockout of HIF-1α is protective against glomerulosclerosis and glomerular type-I collagen accumulation in a mouse podocyte ablation model. Transcriptional analysis of cultured renal cells showed that α2(I) collagen expression is directly regulated by HIF-1α binding to a functional hypoxia-responsive element in its promoter at -335 relative to the transcription start site...
October 2016: Kidney International
Tania Romina Stoyanoff, Juan Pablo Rodríguez, Juan Santiago Todaro, Joaquín Diego Espada, Juan Pablo Melana Colavita, Nora Cristina Brandan, Adriana Mónica Torres, María Victoria Aguirre
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas. There is great interest to know the molecular basis of the tumor biology of ccRCC that might contribute to a better understanding of the aggressive biological behavior of this cancer and to identify early biomarkers of disease. This study describes the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (hypoxia-inducible factor (HIF)-1α, erythropoietin (EPO), vascular endothelial growth factor (VEGF)), their receptors (EPO-R, VEGFR-2), and stearoyl desaturase-1 (SCD-1) in early stages of ccRCC...
July 28, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Henri Leinonen, Maarit Rossi, Antti M Salo, Päivi Tiainen, Jaana Hyvärinen, Marja Pitkänen, Raija Sormunen, Ilkka Miinalainen, Chi Zhang, Raija Soininen, Kari I Kivirikko, Ari Koskelainen, Heikki Tanila, Johanna Myllyharju, Peppi Koivunen
Age-related macular degeneration (AMD), affecting the retinal pigment epithelium (RPE), is the leading cause of blindness in middle-aged and older people in developed countries. Genetic and environmental risk factors have been identified, but no effective cure exists. Using a mouse model we show that a transmembrane prolyl 4-hydroxylase (P4H-TM), which participates in the oxygen-dependent regulation of the hypoxia-inducible factor (HIF), is a potential novel candidate gene for AMD. We show that P4h-tm had its highest expression levels in the mouse RPE and brain, heart, lung, skeletal muscle and kidney...
July 27, 2016: Human Molecular Genetics
S M Keefe, J Hoffman-Censits, R B Cohen, R Mamtani, D Heitjan, S Eliasof, A Nixon, B Turnbull, E G Garmey, O Gunnarsson, M Waliki, J Ciconte, L Jayaraman, A Senderowicz, A B Tellez, M Hennessy, A Piscitelli, D Vaughn, A Smith, N B Haas
BACKGROUND: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle-drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab...
August 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Chiara Ciccarese, Matteo Brunelli, Rodolfo Montironi, Michelangelo Fiorentino, Roberto Iacovelli, Daniel Heng, Giampaolo Tortora, Francesco Massari
The therapeutic landscape of renal cell carcinoma (RCC) has greatly expanded in the last decade. From being a malignancy orphan of effective therapies, kidney cancer has become today a tumor with several treatment options. Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways)...
September 2016: Cancer Treatment Reviews
Tetsuhiro Tanaka
Renal fibrosis is characterized by tubular cell atrophy and accumulation of extracellular matrix. Fibroblast activation becomes evident in areas surrounding atrophic tubules, with rarefaction of peritubular capillaries. Tubulointerstitial hypoxia is the final common pathway in progressive kidney disease. Hypoxia suppresses tubular epithelial growth and leads to failure of remodeling by facilitating dedifferentiation and apoptosis. Profibrotic factors such as transforming growth factor-β (TGF-β) mediate fibroblast activation, and recruited leukocytes, which appear in hypoxic areas, contribute to fibrosis...
July 20, 2016: Medical Molecular Morphology
Johannes C van der Mijn, David J Panka, Andrew K Geissler, Henk M Verheul, James W Mier
Molecular profiling studies of tumor tissue from patients with clear cell renal cell cancer (ccRCC) have revealed extensive metabolic reprogramming in this disease. Associations were found between metabolic reprogramming, histopathologic Fuhrman grade, and overall survival of patients. Large-scale genomics, proteomics, and metabolomic analyses have been performed to identify the molecular players in this process. Genes involved in glycolysis, the pentose phosphate pathway, glutamine metabolism, and lipogenesis were found to be upregulated in renal cell cancer (RCC) specimens as compared to normal tissue...
2016: Cancer & Metabolism
N Shenoy, L Pagliaro
Clear cell renal cell carcinoma (ccRCC) accounts for ∼80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ∼75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Yalcin Solak, Mustafa Cetiner, Dimitrie Siriopol, Kayhan Tarim, Baris Afsar, Adrian Covic, Mehmet Kanbay
Anemia seen in patients with chronic kidney disease is a particular form of 'anemia of chronic disease'. Although multifactorial in origin, erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the primary treatment for anemia in chronic kidney disease. Subsequent clinical observations revealed that these ESA hyporesponsive patients often had increased systemic inflammation as a consequence of their comorbidities. Use of high ESA doses to overcome this ESA hyporesponsiveness posed some concerns regarding associated adverse events of therapy and increased mortality in this special patient population...
2016: Blood Purification
Li Sun, Quan Yuan, Tianhua Xu, Li Yao, Jiangmin Feng, Jianfei Ma, Lining Wang, Changlong Lu, Danan Wang
BACKGROUND/AIMS: Pioglitazone is a type of peroxisome proliferator-activated receptor x03B3; agonist and is capable of alleviating renal ischemia-reperfusion injury. METHODS: A5/6 nephrectomized rat model was established to induce renal impairments mimicking chronic kidney diseases (CKDs). The effect of pioglitazone on renal structure, function, antioxidative capacity, and angiogenesis in the nephrectomized rats was assessed. Moreover, the expression of HIF-1α, eNOS, VEGF, Flt-1 and Flk-1 was determined to reveal the possible pathways through which pioglitazone exerted its beneficial effect on CKDs...
2016: Cellular Physiology and Biochemistry
Felix Preisser, Klaudia Giehl, Margot Rehm, Margarete Goppelt-Struebe
Pharmacological inhibition of oxygen sensing prolyl hydroxylase domain enzymes (PHDs) has been shown to preserve renal structure and function in various models of kidney disease. Since transforming growth factor β-1 (TGFβ-1) is one of the major mediators of kidney injury, we investigated if inhibition of PHDs with subsequent stabilization of hypoxia inducible transcription factors (HIF) might interfere with TGFβ-1 signaling with special emphasis on its target gene connective tissue growth factor (CTGF). Overnight incubation of human renal tubular cells, primary cells and cell lines, with the PDH inhibitor DMOG increased Smad3 expression, but barely affected Smad2...
August 2016: Biochimica et Biophysica Acta
Holger Schmid, Wolfgang Jelkmann
INTRODUCTION: The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs. AREAS COVERED: By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis...
August 2016: Expert Opinion on Investigational Drugs
Fumihiko Okumura, Keiji Uematsu, Stuart D Byrne, Mie Hirano, Akiko Joo-Okumura, Akihiko Nishikimi, Taro Shuin, Yoshinori Fukui, Kunio Nakatsukasa, Takumi Kamura
pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxia-inducible factor α (HIF-α) for proteasomal degradation. Although HIF-α activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-α alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-α-independent pathway in VHL pathogenesis. Here, we show that the transcription factor B-Myb is a pVHL substrate that is degraded via the ubiquitin-proteasome pathway and that vascular endothelial growth factor (VEGF)- and/or platelet-derived growth factor (PDGF)-dependent tyrosine 15 phosphorylation of B-Myb prevents its degradation...
June 15, 2016: Molecular and Cellular Biology
Christopher J Ricketts, Daniel R Crooks, Carole Sourbier, Laura S Schmidt, Ramaprasad Srinivasan, W Marston Linehan
Renal cell carcinoma (RCC) is a heterogeneous disease made up of a number of different cancer types, with distinct histologies, clinical courses, therapeutic responses, and genetic drivers. Germline mutations in 14 genes have been associated with increased risk of RCC and can result in HIF pathway activation, chromatin dysregulation, and altered metabolism. Knowledge of these pathway alterations can inform the development of targeted therapeutic approaches. To view this SnapShot, open or download the PDF.
April 11, 2016: Cancer Cell
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