Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia - PubMed (original) (raw)

Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia

M J Tracz et al. Kidney Int. 2007 Nov.

Abstract

Heme oxygenase-1 may exert cytoprotective effects. In this study we examined the sensitivity of heme oxygenase-1 knockout (HO-1(-/-)) mice to renal ischemia by assessing glomerular filtration rate (GFR) and cytokine expression in the kidney, and inflammatory responses in the systemic circulation and in vital extrarenal organs. Four hours after renal ischemia, the GFR of HO-1(-/-) mice was much lower than that of wild-type mice in the absence of changes in renal blood flow or cardiac output. Eight hours after renal ischemia, there was a marked induction of interleukin-6 (IL-6) mRNA and its downstream signaling effector, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), in the kidney, lung, and heart in HO-1(-/-) mice. Systemic levels of IL-6 were markedly and uniquely increased in HO-1(-/-) mice after ischemia as compared to wild-type mice. The administration of an antibody to IL-6 protected against the renal dysfunction and mortality observed in HO-1(-/-) mice following ischemia. We suggest that the exaggerated production of IL-6, occurring regionally and systemically following localized renal ischemia, in an HO-1-deficient state may underlie the heightened sensitivity observed in this setting.

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Figures

Figure 1

Figure 1. Renal hemodynamics in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

The data demonstrate the following hemodynamic parameters: glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), and filtration fraction (FF). n = 4 in each of the HO-1+/+ and HO-1−/− groups subjected to sham ischemia; n = 6 and n = 8 (GFR), and n = 5 and n = 7 (RBF, RVR, and FF) in HO-1+/+ and HO-1−/− groups subjected to IR respectively. *P< 0.05 versus HO-1+/+ mice subjected to the same condition.

Figure 2

Figure 2. Cardiac function in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

The data demonstrate the following: heart rate (beats per minute), circumferential shortening velocity (circumferences/s), fractional shortening (%), and cardiac output (ml/min/30 g). n = 5 in each of the HO-1+/+ Sham and HO-1+/+ IR groups, and n = 6 in each of HO-1−/− Sham and HO-1−/− IR groups.

Figure 3

Figure 3. HO-1 expression in the kidney 4 h after sham or IR injury

Upper panel: Western analysis for HO-1 protein expression in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham). Each lane represents protein extracted from a single kidney of an individual mouse. Equivalency of protein loading was verified by Ponceau staining (not shown). Lower panel: HO-1 mRNA by quantitative real-time reverse transcriptase-PCR in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham). n = 4 in each of the HO-1+/+ Sham and HO-1−/− Sham groups, and n = 6 and n = 8 in HO-1+/+ IR and HO-1−/− IR groups respectively.

Figure 4

Figure 4. IL-6 mRNA determination by quantitative real-time reverse transcriptase-PCR in the kidney in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

n = 4 and n = 5 in the HO-1+/+ Sham and HO-1−/− Sham groups respectively, and n = 8 and n = 7 in the HO-1+/+ IR and HO-1−/− IR groups respectively. *P< 0.05 versus HO-1+/+ mice subjected to the same condition.

Figure 5

Figure 5. Western analysis for pSTAT3 and STAT3 expression in the kidney in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

Each lane represents protein extracted from a single kidney of an individual mouse, and equivalency of protein loading was verified by immunoblotting for _β_-actin.

Figure 6

Figure 6. Serum levels of IL-6 in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

n = 4 and n = 5 in the HO-1+/+ Sham and HO-1−/− Sham groups respectively, and n = 8 and n = 7 in the HO-1+/+ IR and HO-1−/− IR groups respectively. *P< 0.05 versus HO-1+/+ mice subjected to the same condition.

Figure 7

Figure 7. Serum levels of IL-12 (p40) in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

n = 4 and n = 5 in the HO-1+/+ Sham and HO-1−/− Sham groups respectively, and n = 8 and n = 7 in the HO-1+/+ IR and HO-1−/− IR groups respectively. *P< 0.05 versus HO-1+/+ mice subjected to the same condition.

Figure 8

Figure 8. Serum levels of IL-5 and macrophage inflammatory protein (MIP)-1a in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

n = 4 and n = 5 in the HO-1+/+ Sham and HO-1−/− Sham groups respectively, and n = 8 and n = 7 in the HO-1+/+ IR and HO-1−/− IR groups respectively. *P< 0.05 versus HO-1+/+ mice subjected to the same condition.

Figure 9

Figure 9. IL-6 mRNA determination by quantitative real-time reverse transcriptase-PCR in the heart and lung in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

For studies in either organ, n = 4 and n = 5 in the HO-1+/+ Sham and HO-1−/− Sham groups respectively, and n = 8 and n = 7 in the HO-1+/+ IR and HO-1−/− IR groups respectively. *P< 0.05 versus HO-1+/+ mice subjected to the same condition.

Figure 10

Figure 10. Western analysis for pSTAT3 and STAT3 expression in the lung in HO-1+/+ and HO-1−/− mice subjected to ischemia–reperfusion injury (IR) or sham ischemia (Sham)

Each lane represents protein extracted from a single lung of an individual mouse, and equivalency of protein loading was verified by immunoblotting for _β_-actin.

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