Pan Szu-Yu, Tsai Pei-Zhen, Chou Yu-Hsiang, Chang Yu-Ting, Chang Fan-Chi, Chiu Yen-Ling, Chiang Wen-Chih, Hsu Tien, Chen Yung-Ming, Chu Tzong-Shinn, Lin Shuei-Liong
Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Kidney Int. 2021 Jun;99(6):1354-1368. doi: 10.1016/j.kint.2021.01.017. Epub 2021 Mar 31.
Prolyl hydroxylase domain enzyme (PHD) inhibitors are effective in the treatment of chronic kidney disease (CKD)-associated anemia by stabilizing hypoxia inducible factor (HIF), thereby increasing erythropoietin and consequently erythropoiesis. However, concern for CKD progression needs to be addressed in clinical trials. Although pre-clinical studies showed an anti-inflammatory effect in kidney disease models, the effect of PHD inhibitors on kidney fibrosis was inconsistent probably because the effects of HIF are cell type and context dependent. The major kidney erythropoietin-producing cells are pericytes that produce erythropoietin through HIF-2α-dependent gene transcription. The concern for the impact of HIF in pericytes on kidney fibrosis arises from the fact that pericytes are the major precursor cells of myofibroblasts in CKD. Since cells expressing Gli1 fulfill the morphologic and anatomic criteria for pericytes, we induced Gli1 cell-specific HIF stabilization or knockout to study the impact of HIF in pericytes on kidney pathology of mice with or without fibrotic injury induced by unilateral ureteral obstruction. Compared with the littermate controls, mice with pericyte-specific HIF stabilization due to von Hippel-Lindau protein or PHD2 knockout showed increased serum erythropoietin and polycythemia rather than a discernible difference in kidney fibrosis. Compared with Gli1 pericytes sorted from littermate controls, Gli1 pericytes sorted from PHD2 knockout mice showed increased erythropoietin gene expression rather than discernible changes in Col1a1 or Acta2 expression. Furthermore, pericyte-specific knockout of HIF-1α or HIF-2α did not affect kidney fibrosis. Thus, our study supports the absence of negative effects of PHD inhibitors on kidney fibrosis of mice despite HIF stabilization in pericytes.
脯氨酰羟化酶结构域酶（PHD）抑制剂可通过稳定缺氧诱导因子（HIF）来有效治疗慢性肾脏病（CKD）相关贫血，从而增加促红细胞生成素，进而促进红细胞生成。然而，在临床试验中需要解决对CKD进展的担忧。尽管临床前研究显示在肾脏疾病模型中有抗炎作用，但PHD抑制剂对肾纤维化的作用并不一致，这可能是因为HIF的作用取决于细胞类型和背景。肾脏中产生促红细胞生成素的主要细胞是周细胞，其通过HIF-2α依赖的基因转录产生促红细胞生成素。对周细胞中HIF对肾纤维化影响的担忧源于周细胞是CKD中肌成纤维细胞的主要前体细胞这一事实。由于表达Gli1的细胞符合周细胞的形态学和解剖学标准，我们诱导Gli1细胞特异性HIF稳定或敲除，以研究周细胞中HIF对单侧输尿管梗阻诱导的有无纤维化损伤的小鼠肾脏病理的影响。与同窝对照相比，因冯·希佩尔-林道蛋白或PHD2敲除而导致周细胞特异性HIF稳定的小鼠血清促红细胞生成素增加且出现红细胞增多症，而非肾纤维化有明显差异。与从同窝对照中分选的Gli1周细胞相比，从PHD2敲除小鼠中分选的Gli1周细胞促红细胞生成素基因表达增加，而非Col1a1或Acta2表达有明显变化。此外，周细胞特异性敲除HIF-1α或HIF-2α并不影响肾纤维化。因此，我们的研究支持尽管周细胞中HIF稳定，但PHD抑制剂对小鼠肾纤维化无负面影响。
