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HIF in renal disease

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https://www.readbyqxmd.com/read/29655605/physiology-and-pathophysiology-of-renal-erythropoietin-producing-cells
#1
REVIEW
Hong-Mou Shih, Chih-Jen Wu, Shuei-Liong Lin
Anemia is a common complication and contributes to increased morbidity and mortality in chronic kidney disease (CKD) patients. Whereas there has been a significant improvement of understanding the underlying mechanism of erythropoiesis, the treatment of renal anemia is still restricted to erythropoietin (EPO)-stimulating agents. The purpose of this article is to review the physiology of erythropoiesis, functional role of EPO and underlying molecular and cellular basis that regulate EPO production. Regulation of EPO production is at mRNA level...
April 11, 2018: Journal of the Formosan Medical Association, Taiwan Yi Zhi
https://www.readbyqxmd.com/read/29597186/levels-of-endocan-angiopoietin-2-and-hypoxia-inducible-factor-1a-in-patients-with-autosomal-dominant-polycystic-kidney-disease-and-different-levels-of-renal-function
#2
Vassilios Raptis, Constantinos Bakogiannis, Charalampos Loutradis, Afroditi K Boutou, Ioanna Lampropoulou, Elena Intzevidou, Athanasios Sioulis, Elias Balaskas, Pantelis A Sarafidis
BACKGROUND: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. METHODS: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45-70 mL/min/1...
March 29, 2018: American Journal of Nephrology
https://www.readbyqxmd.com/read/29595810/genotype-and-phenotype-correlation-in-von-hippel-lindau-disease-based-on-alteration-of-the-hif-%C3%AE-binding-site-in-vhl-protein
#3
Sheng-Jie Liu, Jiang-Yi Wang, Shuang-He Peng, Teng Li, Xiang-Hui Ning, Bao-An Hong, Jia-Yuan Liu, Peng-Jie Wu, Bo-Wen Zhou, Jing-Cheng Zhou, Nie-Nie Qi, Xiang Peng, Jiu-Feng Zhang, Kai-Fang Ma, Lin Cai, Kan Gong
PurposeVon Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL).MethodsVHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.ResultsMissense mutations conferred an increased risk of pheochromocytoma (HR = 1...
March 29, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29575006/first-in-man-proof-of-concept-study-with-molidustat-a-novel-selective-oral-hif-prolyl-hydroxylase-inhibitor-for-the-treatment-of-renal-anaemia
#4
M Böttcher, S Lentini, E R Arens, A Kaiser, D van der Mey, U Thuss, D Kubitza, G Wensing
AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose-dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and the effect on EPO levels after single oral doses of molidustat in healthy male volunteers. METHODS: This was a single centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study...
March 25, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29569190/hif-stabilizers-in-the-management-of-renal-anemia-from-bench-to-bedside-to-pediatrics
#5
REVIEW
Dalvir Kular, Iain C Macdougall
Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolyl-hydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene...
March 22, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
https://www.readbyqxmd.com/read/29501969/hypoxia-inducible-factor-1%C3%AE-directs-renal-regeneration-induced-by-decellularized-scaffolds
#6
Yaling Yu, Haomin Cui, Chuan Chen, Gen Wen, Jia Xu, Binbin Zheng, Jianse Zhang, Chunyang Wang, Yimin Chai, Jin Mei
Although mammalian kidney regeneration has been reported to occur throughout life, mature kidneys in mammals are not thought to regenerate sufficiently, particularly glomeruli. In our previous work, we found that renal regeneration could be enhanced by decellularized renal scaffolds after partial nephrectomy. In this study, we verified that the enhanced renal regeneration mediated by decellularized scaffolds could be attributed to regenerated glomeruli, which were counted both indirectly and directly under a microscope...
May 2018: Biomaterials
https://www.readbyqxmd.com/read/29485740/discovery-of-molidustat-bay-85-3934-a-small-molecule-oral-hif-prolyl-hydroxylase-hif-ph-inhibitor-for-the-treatment-of-renal-anemia
#7
Hartmut Beck, Mario Jeske, Kai Thede, Friederike Stoll, Ingo Flamme, Metin Akbaba, Jens-Kerim Ergüden, Gunter Karig, Jörg Keldenich, Felix Oehme, Hans-Christian Militzer, Ingo V Hartung, Uwe Thuss
Small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment option for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased EPO expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, SAR and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia...
February 27, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29467323/von-hippel-lindau-mutations-disrupt-vascular-patterning-and-maturation-via-notch
#8
Alexandra Arreola, Laura Beth Payne, Morgan H Julian, Aguirre A de Cubas, Anthony B Daniels, Sarah Taylor, Huaning Zhao, Jordan Darden, Victoria L Bautch, W Kimryn Rathmell, John C Chappell
Von Hippel-Lindau (VHL) gene mutations induce neural tissue hemangioblastomas, as well as highly vascularized clear cell renal cell carcinomas (ccRCCs). Pathological vessel remodeling arises from misregulation of HIFs and VEGF, among other genes. Variation in disease penetrance has long been recognized in relation to genotype. We show Vhl mutations also disrupt Notch signaling, causing mutation-specific vascular abnormalities, e.g., type 1 (null) vs. type 2B (murine G518A representing human R167Q). In conditional mutation retina vasculature, Vhl-null mutation (i...
February 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29464030/under-expression-of-ck2%C3%AE-subunit-in-ccrcc-represents-a-complementary-biomarker-of-p-stat3-ser727-that-correlates-with-patient-survival
#9
Jordi Vilardell, Estefania Alcaraz, Eduard Sarró, Enric Trilla, Thaïs Cuadros, Inés de Torres, Maria Plana, Santiago Ramón Y Cajal, Lorenzo A Pinna, Maria Ruzzene, Juan Morote, Anna Meseguer, Emilio Itarte
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of renal cancer. STAT3 pathway is altered in these tumors and p-STAT3 Ser727 is an independent prognostic factor for ccRCC. Protein kinase CK2 is altered in different types of tumors and overexpression of CK2α is considered predictive of bad prognosis and metastatic risk. CK2 subunits analyses in ccRCC samples showed increased CK2α/α' nuclear content in all cases, but decreased cytosolic CK2β (CK2βcyt) levels in the more advanced tumors...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29463398/quel-pourrait-%C3%A3%C2%AAtre-le-futur-de-la-prise-en-charge-de-l%C3%A2-an%C3%A3-mie-dans-l%C3%A2-insuffisance-r%C3%A3-nale-chronique
#10
O Hermine, Th Maciel, I Moura
Erythropoietin (EPO) plays an essential role in the regulation of erythropoiesis. Its production is under the control of the Hypoxia Inducible Factor (HIF) protein whose stability varies according to the oxygen level. During chronic renal failure, EPO deficiency is the main cause of anemia, but other factors such as iron deficiency and inflammatory syndrome are also involved. More recently, it is hypothesized that other factors such an excess of GDF-11 production may be also involved. Thus, beside Epo treatment HIF and GDF-11 are potentially new therapeutic targets in anemia of chronic kidney disease...
June 2017: Néphrologie & Thérapeutique
https://www.readbyqxmd.com/read/29363499/metabolic-profiling-of-the-novel-hypoxia-inducible-factor-2-%C3%AE-inhibitor-pt2385-in-vivo-and-in-vitro
#11
Cen Xie, Xiaoxia Gao, Dongxue Sun, Youbo Zhang, Kristopher W Krausz, Xuemei Qin, Frank J Gonzalez
PT2385 is a first-in-class, selective small-molecule inhibitor of hypoxia-inducible factor-2 α (HIF-2 α ) developed for the treatment of advanced clear cell renal cell carcinoma. Preclinical results demonstrated that PT2385 has potent antitumor efficacy in mouse xenograft models of kidney cancer. It also has activity toward metabolic disease in a mouse model. However, no metabolism data are currently publically available. It is of great importance to characterize the metabolism of PT2385 and identify its effect on systemic homeostasis in mice...
April 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
#12
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
#13
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...
March 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
#14
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...
May 2018: Angiogenesis
https://www.readbyqxmd.com/read/29261470/science-to-practice-can-functional-mr-imaging-be-useful-in-the-evaluation-of-cardiorenal-syndrome
#15
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
#16
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
#17
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
#18
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
#19
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 histopathologic studies are performed to prove, localize, treat, and monitor disease progression. Improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (<1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
January 2018: Endocrine Practice
https://www.readbyqxmd.com/read/29113209/prognostic-value-of-copper-transporter-1-expression-in-patients-with-clear-cell-renal-cell-carcinoma
#20
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
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