Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis

Abstract

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 preclinical 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-2a-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 þ cellspecific 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 þ pericytes sorted from littermate controls, Gli1 þ 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-1a or HIF-2a 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.

Contribution of Oxidative Stress to HIF‐1‐Mediated Profibrotic Changes during the Kidney Damage

“…The effects of HIFs may be cell type and context dependent. HIF-2 α may also be a candidate for studying renal fibrosis [ 17 , 18 ]. However, HIF-3 is less well known.…”

Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells

“…This study demonstrated that PHDi could not increase HIF2α expression of 10T1/2 cells in the presence of TGF-β1. However, PHDi emerges as a promising therapeutic agent for the renal anemia principally through stabilizing HIF [ 47 – 49 ]. One of the plausible reasons would be that a continuous spectrum existed between normal kidney pericytes and scar-producing myofibroblasts in fibrotic kidneys [ 3 , 20 ].…”

Pleotropic effects of hypoxia-inducible factor-prolyl hydroxylase domain inhibitors: are they clinically relevant?

“…Previous study reported that Gli1 is one of the markers of pericyte and the ablation of Gli1 + -cell attenuated renal fibrosis [ 36 ]. Hence, we induced Gli1 + cell-specific HIF stabilization via Vhl or Phd2 knockout showed increased serum erythropoietin and polycythemia without a significant difference in profibrotic gene expression and kidney fibrosis [ 37 ]. However, because there are many other markers of fibroblasts/pericytes such as platelet-derived growth factor (PDGF) receptor β, CD73, smooth muscle myosin protein, and tenascin-C which manifest as different lineages, we need further study to clarify the effect of HIF activation in pericytes from other lineages in various models (ischemia-reperfusion, adenine-induced CKD, aristolochic acid nephropathy, and diabetic nephropathy) and clinical trials to observe the effect of PHD inhibitors on renal fibrosis [ 38 ].…”