Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension

Abstract

Despite the increasing need to identify and quantify tissue oxygenation at the cellular level, relatively few methods have been available. In this study, we developed a new hypoxia-responsive reporter vector using a hypoxia-responsive element of the 5 vascular endothelial growth factor untranslated region and generated a novel hypoxia-sensing transgenic rat. We then applied this animal model to the detection of tubulointerstitial hypoxia in the diseased kidney. With this model, we were able to identify diffuse cortical hypoxia in the puromycin aminonucleosideinduced nephrotic syndrome and focal and segmental hypoxia in the remnant kidney model. Expression of the hypoxia-responsive transgene increased throughout the observation period, reaching 2.2-fold at 2 weeks in the puromycin aminonucleoside model and 2.6-fold at 4 weeks in the remnant kidney model, whereas that of vascular endothelial growth factor showed a mild decrease, reflecting distinct behaviors of the two genes. The degree of hypoxia showed a positive correlation with microscopic tubulointerstitial injury in both models. Finally, we identified the localization of proliferating cell nuclear antigen-positive, ED-1-positive, and terminal dUTP nick-end labeled-positive cells in the hypoxic cortical area in the remnant kidney model. We propose here a possible pathological tie between chronic tubulointerstitial hypoxia and progressive glomerular diseases. (Am J

Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease

“…In summary, activation of the HIF signaling pathway has the It is interesting to note that in our study the RNA and protein expression of VEGF-A was suppressed in patients with progressive renal failure, despite activation of the HIF transcription factors. In line with this finding are results by Tanaka et al, 36 which also described a decreased VEGF protein expression despite HIF activation in two rat models of chronic renal failure. Recent publications also suggest a decline of VEGF-A expression in progressive diabetic nephropathy.…”

Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model

“…Activation of HIF by cobalt was confirmed by immunodetection of the transgene in 'hypoxiaresponsive element (HRE)-luciferase' transgenic rats developed recently in our laboratory 28 (Figure 2a). Figure 2 Activation of HIF and induction of HIF-regulated genes by cobalt.…”

“…17 However, some controversy remains as to whether hypoxia is still present in the advanced stages of this model. 28,29 In this regard, pimonidazole staining was conducted to visualize hypoxia at week 9 of the remnant kidney ( Figure 1). In areas with moderate damage, hypoxic areas appeared to extend from the outer medulla to the inner cortex (b), as compared to controls (a), while in regions with severe injury, hypoxic signals were evident in dilated, proximal tubules (c).…”

Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis

“…To demonstrate hypoxia in the clipped kidney, we used male "hypoxia-sensing" transgenic rats of Wistar strain (39). These are transgenic rats harboring a transgene composed of hypoxia response element (HRE; enhancer) and the FLAG-tagged luciferase reporter gene, allowing us to detect hypoxic cells through hypoxia-inducible factor (HIF)-mediated cellular hypoxic response.…”