FibroGen, Inc., San Francisco, CA, United States of America.
PLoS One. 2021 Aug 2;16(8):e0255022. doi: 10.1371/journal.pone.0255022. eCollection 2021.
Prolyl hydroxylase (PH) enzymes control the degradation of hypoxia-inducible factor (HIF), a transcription factor known to regulate erythropoiesis, angiogenesis, glucose metabolism, cell proliferation, and apoptosis. HIF-PH inhibitors (HIF-PHIs) correct anemia in patients with renal disease and in animal models of anemia and kidney disease. However, the effects of HIF-PHIs on comorbidities associated with kidney disease remain largely unknown. We evaluated the effects of the HIF-PHI FG-2216 in obese ZSF1 (Ob-ZSF1) rats, an established model of kidney failure with metabolic syndrome. Following unilateral nephrectomy (Nx) at 8 weeks of age, rats were treated with 40 mg/kg FG-2216 or vehicle by oral gavage three times per week for up to 18 weeks. FG-2216 corrected blood hemoglobin levels and improved kidney function and histopathology in Nx-Ob-ZSF1 rats by increasing the glomerular filtration rate, decreasing proteinuria, and reducing peritubular fibrosis, tubular damage, glomerulosclerosis and mesangial expansion. FG-2216 increased renal glucose excretion and decreased body weight, fat pad weight, and serum cholesterol in Nx-Ob-ZSF1 rats. Additionally, FG-2216 corrected hypertension, improved diastolic and systolic heart function, and reduced cardiac hypertrophy and fibrosis. In conclusion, the HIF-PHI FG-2216 improved renal and cardiovascular outcomes, and reduced obesity in a rat model of kidney disease with metabolic syndrome. Thus, in addition to correcting anemia, HIF-PHIs may provide renal and cardiac protection to patients suffering from kidney disease with metabolic syndrome.
脯氨酰羟化酶（PH）酶控制缺氧诱导因子（HIF）的降解，HIF 是一种已知调节红细胞生成、血管生成、葡萄糖代谢、细胞增殖和细胞凋亡的转录因子。HIF-PH 抑制剂（HIF-PHI）可纠正肾病患者和贫血及肾病动物模型中的贫血。然而，HIF-PHI 对与肾病相关的合并症的影响在很大程度上仍不清楚。我们评估了 HIF-PHI FG-2216 在肥胖 ZSF1（Ob-ZSF1）大鼠中的作用，Ob-ZSF1 大鼠是一种具有代谢综合征的肾衰竭的成熟模型。在 8 周龄时进行单侧肾切除术（Nx）后，大鼠每周通过口服灌胃接受 40mg/kg FG-2216 或载体治疗长达 18 周。FG-2216 通过增加肾小球滤过率、减少蛋白尿和减少肾小管周围纤维化、肾小管损伤、肾小球硬化和系膜扩张，纠正 Nx-Ob-ZSF1 大鼠的血液血红蛋白水平并改善肾功能和组织病理学。FG-2216 增加了肾脏葡萄糖排泄，并降低了 Nx-Ob-ZSF1 大鼠的体重、脂肪垫重量和血清胆固醇。此外，FG-2216 纠正了高血压，改善了舒张和收缩心功能，并减少了心脏肥大和纤维化。总之，HIF-PHI FG-2216 改善了代谢综合征肾病大鼠的肾脏和心血管结局，并减轻了肥胖。因此，除了纠正贫血外，HIF-PHI 还可能为患有代谢综合征肾病的患者提供肾脏和心脏保护。
