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Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ.

Yamaguchi J, Tanaka T, Eto N, Nangaku M - Kidney Int. (2015)

Bottom Line: CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys.In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity.Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

ABSTRACT
Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1β in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases.

No MeSH data available.


Related in: MedlinePlus

Hypoxia and inflammation coexist in kidney. (a) Macrophage infiltration was visualized by endothelin-1 staining for (A) control, (B) I/R injury, (C) cisplatin nephrotoxicity, (D) RK-4w, and (E) RAS day 7 kidneys. Original magnification, × 400. Bar=30 μm. (b) Real-time qRT-PCR analysis of the renal cortex for inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein-1 (MCP-1)), and HIF-1 target genes (vascular endothelial growth factor (VEGF), angiopoietin-like 4 (ANPLT4), hemeoxygenase-1 (HO-1), and superoxidase dismutase 1 (SOD1)) were performed in cisplatin nephrotoxicity (control group, n=5; cisplatin group, n=5), I/R injury (control group, n=6; I/R group, n=6), RK-4w (control group, n=5; RK-4w group, n=5), and RAS d7 (control group, n=6; RAS group, n=6). Bar graph (combined results from two independent experiments, shown as mean±s.d.) statistics performed using Student's t-test. *P<0.05 and **P<0.01.
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fig4: Hypoxia and inflammation coexist in kidney. (a) Macrophage infiltration was visualized by endothelin-1 staining for (A) control, (B) I/R injury, (C) cisplatin nephrotoxicity, (D) RK-4w, and (E) RAS day 7 kidneys. Original magnification, × 400. Bar=30 μm. (b) Real-time qRT-PCR analysis of the renal cortex for inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein-1 (MCP-1)), and HIF-1 target genes (vascular endothelial growth factor (VEGF), angiopoietin-like 4 (ANPLT4), hemeoxygenase-1 (HO-1), and superoxidase dismutase 1 (SOD1)) were performed in cisplatin nephrotoxicity (control group, n=5; cisplatin group, n=5), I/R injury (control group, n=6; I/R group, n=6), RK-4w (control group, n=5; RK-4w group, n=5), and RAS d7 (control group, n=6; RAS group, n=6). Bar graph (combined results from two independent experiments, shown as mean±s.d.) statistics performed using Student's t-test. *P<0.05 and **P<0.01.

Mentions: These facts led us to hypothesize that tissue inflammation might fine-tune HIF-1 through CEBPD expression. In the kidney, inflammation is mediated by resident tubular cells and inflammatory cells, most commonly by macrophages.30, 31 Macrophages are present in the tubulointerstitium of all of the above-indicated hypoxic kidney models (Figure 4a). Macrophages and tubular cells under inflammatory conditions produce various cytokines and chemokines, including IL-1β, TNF-α, and monocyte chemotactic protein-1. These were confirmed in all the above hypoxic kidney models by real-time quantitative (q)RT-PCR of the diseased renal cortex (Figure 4b). Endogenous HIF-1 target genes, including ANPLT4 (angiopoietin-like 4), VEGF, SOD1 (superoxidase dismutase 1), and HO-1 (hemeoxygenase-1), were overall upregulated except for the RK model, in which the insufficient expression of HIF-target genes is reported (Figure 4b).32 This confirmed that inflammation and hypoxia coexist and may have interactions in kidney diseases.


Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ.

Yamaguchi J, Tanaka T, Eto N, Nangaku M - Kidney Int. (2015)

Hypoxia and inflammation coexist in kidney. (a) Macrophage infiltration was visualized by endothelin-1 staining for (A) control, (B) I/R injury, (C) cisplatin nephrotoxicity, (D) RK-4w, and (E) RAS day 7 kidneys. Original magnification, × 400. Bar=30 μm. (b) Real-time qRT-PCR analysis of the renal cortex for inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein-1 (MCP-1)), and HIF-1 target genes (vascular endothelial growth factor (VEGF), angiopoietin-like 4 (ANPLT4), hemeoxygenase-1 (HO-1), and superoxidase dismutase 1 (SOD1)) were performed in cisplatin nephrotoxicity (control group, n=5; cisplatin group, n=5), I/R injury (control group, n=6; I/R group, n=6), RK-4w (control group, n=5; RK-4w group, n=5), and RAS d7 (control group, n=6; RAS group, n=6). Bar graph (combined results from two independent experiments, shown as mean±s.d.) statistics performed using Student's t-test. *P<0.05 and **P<0.01.
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fig4: Hypoxia and inflammation coexist in kidney. (a) Macrophage infiltration was visualized by endothelin-1 staining for (A) control, (B) I/R injury, (C) cisplatin nephrotoxicity, (D) RK-4w, and (E) RAS day 7 kidneys. Original magnification, × 400. Bar=30 μm. (b) Real-time qRT-PCR analysis of the renal cortex for inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein-1 (MCP-1)), and HIF-1 target genes (vascular endothelial growth factor (VEGF), angiopoietin-like 4 (ANPLT4), hemeoxygenase-1 (HO-1), and superoxidase dismutase 1 (SOD1)) were performed in cisplatin nephrotoxicity (control group, n=5; cisplatin group, n=5), I/R injury (control group, n=6; I/R group, n=6), RK-4w (control group, n=5; RK-4w group, n=5), and RAS d7 (control group, n=6; RAS group, n=6). Bar graph (combined results from two independent experiments, shown as mean±s.d.) statistics performed using Student's t-test. *P<0.05 and **P<0.01.
Mentions: These facts led us to hypothesize that tissue inflammation might fine-tune HIF-1 through CEBPD expression. In the kidney, inflammation is mediated by resident tubular cells and inflammatory cells, most commonly by macrophages.30, 31 Macrophages are present in the tubulointerstitium of all of the above-indicated hypoxic kidney models (Figure 4a). Macrophages and tubular cells under inflammatory conditions produce various cytokines and chemokines, including IL-1β, TNF-α, and monocyte chemotactic protein-1. These were confirmed in all the above hypoxic kidney models by real-time quantitative (q)RT-PCR of the diseased renal cortex (Figure 4b). Endogenous HIF-1 target genes, including ANPLT4 (angiopoietin-like 4), VEGF, SOD1 (superoxidase dismutase 1), and HO-1 (hemeoxygenase-1), were overall upregulated except for the RK model, in which the insufficient expression of HIF-target genes is reported (Figure 4b).32 This confirmed that inflammation and hypoxia coexist and may have interactions in kidney diseases.

Bottom Line: CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys.In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity.Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

ABSTRACT
Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1β in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases.

No MeSH data available.


Related in: MedlinePlus