Effects of HIF prolyl hydroxylase inhibition in models of chronic kidney disease

HIF 脯氨酰羟化酶抑制对慢性肾病模型的影响

• 批准号: 221621894
• 负责人: Professor Dr. Carsten Willam
• 金额: --
• 依托单位: Pathologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221621894?language=en
• 关键词: Effects; HIF; prolyl; hydroxylase; inhibition

Chronic kidney diseases are regularly associated with chronic hypoxia due to concomitant pathophysiological processes like interstitial fibrosis and capillary rarefaction. Under hypoxia, a central regulatory factor is the transcription factor Hypoxia Inducible Factor (HIF) which controls numerous cellular processes like angiogenesis, erythropoiesis or glycolysis, which altogether allows tissues to adapt to low oxygen concentrations. In order to induce erythropoietin, newly developed HIF stabilizers are already under clinical evaluation. On the other hand HIF has also been associated with profibrotic, potentially deleterious effects. To this end, it is not clear which effects HIF stabilisation by Prolyl hydroxylase inhibition will have in progressive kidney disease and if HIF stabilisation may have protective effects. HIF Prolyl hydroxylases hydroxylate the HIF protein which targets it for cellular proteasomal degradation. In complementary mouse models of chronic kidney diseases the functional importance of HIF stabilisation in the kidney should be analyzed. Firstly, the prolyl hydroxylase-2 or the vhl gene will be genetically inactivated and secondly newly synthesized ketoglutarate analogues will be applied, which selectively can inhibit the PHDs in renal epithelial cells.

慢性肾脏疾病通常与慢性缺氧有关，这是由于伴随的病理生理过程，如间质纤维化和毛细血管稀疏。在缺氧条件下，一个中心调节因子是转录因子缺氧诱导因子（HIF），它控制着许多细胞过程，如血管生成、红细胞生成或糖酵解，这些过程共同允许组织适应低氧浓度。为了诱导促红细胞生成素，新开发的HIF稳定剂已经在临床评估中。另一方面，HIF也与促纤维化、潜在的有害作用相关。为此，尚不清楚通过脯氨酰羟化酶抑制的HIF稳定化在进行性肾病中将具有何种作用，以及HIF稳定化是否可能具有保护作用。HIF脯氨酰羟化酶使HIF蛋白羟化，其靶向HIF蛋白用于细胞蛋白酶体降解。在慢性肾脏疾病的补充小鼠模型中，应分析HIF稳定在肾脏中的功能重要性。首先，脯氨酰羟化酶-2或vhl基因将被遗传失活，其次，新合成的酮戊二酸类似物将被应用，其可以选择性地抑制肾上皮细胞中的PHD。

项目成果

Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult

• DOI: 10.1007/s00424-014-1667-z
• 发表时间: 2015-01
• 期刊: Pflügers Archiv - European Journal of Physiology
• 作者: Melanie Vogler;A. Zieseniss;Amke R. Hesse;Elif Levent;M. Tiburcy;E. Heinze;N. Burzlaff;G. Schley

HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress.

• DOI: 10.1182/blood-2012-12-471185
• 发表时间: 2013-06
• 期刊: Blood
• 影响因子: 20.3
• 作者: R. Singh;K. Franke;Joanna Kalucka;S. Mamlouk;A. Muschter;Agnieszka Gembarska;T. Grinenko;C. Willam;R. Naumann;K. Anastassiadis;K. Anastassiadis;A. F. Stewart;S. Bornstein;T. Chavakis;G. Breier;Claudia Waskow;B. Wielockx