Hypoxia-inducible factor signaling in the development of tissue fibrosis

Abstract

Capillary rarefaction is a hallmark of fibrotic diseases and results in reduced blood perfusion and oxygen delivery. In the kidney, tubulointerstitial fibrosis, which leads to the destruction of renal tissue and the irreversible loss of kidney function, is associated with hypoxia and the activation of Hypoxia-Inducible-Factor (HIF) signaling. HIF-1 and HIF-2 are basic-helix-loop-helix transcription factors that allow cells to survive in a low oxygen environment by regulating energy metabolism, vascular remodeling, erythropoiesis, cellular proliferation and apoptosis. Recent studies suggest that HIF activation promotes epithelial to mesenchymal transition (EMT) and renal fibrogenesis. These findings raise the possibility that the spectrum of HIF activated biological responses to hypoxic stress may differ under conditions of acute and chronic hypoxia. Here we discuss the role of HIF signaling in the pathogenesis and progression of chronic kidney disease.

Figure 1

Detection of nuclear HIF-1α in paraffin embedded renal biopsy tissue sections from a patient with IgA nephropathy. (A) Masson Trichrome (MT) stain. Blue staining indicates the presence of collagen. (B) Immunohistochemical stain for HIF-1α in an adjacent section. Arrows point to tubular cells expressing HIF-1α. (C) Immunohistochemical stain for FSp1. Arrows point to FSp1-positive cells associated with fibrotic areas. Magnification ×200.

Figure 2

Hypoxia induces a mesenchymal phenotype in primary renal epithelial cells. Primary cells were lineage-tagged with a lacZ reporter using Cre-loxP mediated recombination and de novo expression of fibroblast marker FSp1 was monitored by immunoflourescence. Hypoxia (5 days, 1% O₂) increased the percentage of FSp1 expressing cells. (A–C) Shown is immunoflourescence staining for lacZ in red (A) and for FSp1 in green (B). Lineage-tagged epithelial cells, which stain for both lacZ and FSp1 and fluoresce in yellow are shown in (C). De novo expression of FSp1 indicates that these cells have undergone transition to a mesenchymal phenotype. (D and E) LacZ and FSp1 immunofluorescence stain of primary cells exposed to normoxia (D) and hypoxia (E). The percentage of epithelial cells that express FSp1 de novo increases under hypoxia (yellow fluorescence) as illustrated in (E). For technical details of this analysis see Higgins et al., magnification ×400.

Figure 3

Schematic suggesting hypoxia-regulated biological processes and mechanisms through which HIF activation may promote renal fibrogenesis. HIF signaling appears to play a pivotal role in the regulation of inflammatory responses, however the role of HIF activation with regard to renal injury mediated by inflammatory cells is unclear. Because of its important role in the initiation and maintenance of kidney injury we have included `inflammation' in this schematic.