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, 26 (10), 2378-87

Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

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Regulation of Mitochondrial Dynamics by Dynamin-Related Protein-1 in Acute Cardiorenal Syndrome

Maki Sumida et al. J Am Soc Nephrol.

Abstract

Experimental evidence has clarified distant organ dysfunctions induced by AKI. Crosstalk between the kidney and heart, which has been recognized recently as cardiorenal syndrome, appears to have an important role in clinical settings, but the mechanisms by which AKI causes cardiac injury remain poorly understood. Both the kidney and heart are highly energy-demanding organs that are rich in mitochondria. Therefore, we investigated the role of mitochondrial dynamics in kidney-heart organ crosstalk. Renal ischemia reperfusion (IR) injury was induced by bilateral renal artery clamping for 30 min in 8-week-old male C57BL/6 mice. Electron microscopy showed a significant increase of mitochondrial fragmentation in the heart at 24 h. Cardiomyocyte apoptosis and cardiac dysfunction, evaluated by echocardiography, were observed at 72 h. Among the mitochondrial dynamics regulating molecules, dynamin-related protein 1 (Drp1), which regulates fission, and mitofusin 1, mitofusin 2, and optic atrophy 1, which regulate fusion, only Drp1 was increased in the mitochondrial fraction of the heart. A Drp1 inhibitor, mdivi-1, administered before IR decreased mitochondrial fragmentation and cardiomyocyte apoptosis significantly and improved cardiac dysfunction induced by renal IR. This study showed that renal IR injury induced fragmentation of mitochondria in a fission-dominant manner with Drp1 activation and subsequent cardiomyocyte apoptosis in the heart. Furthermore, cardiac dysfunction induced by renal IR was improved by Drp1 inhibition. These data suggest that mitochondrial fragmentation by fission machinery may be a new therapeutic target in cardiac dysfunction induced by AKI.

Keywords: acute renal failure; apoptosis; cardiovascular; mitochondria.

Figures

Figure 1.
Figure 1.
Mitochondrial fragmentation in the heart induced by renal IR injury. (A) Electron microscopy showed renal IR increased fragmented mitochondria in the cardiomyocytes after 24 h. Original magnification ×10,000. (B) The area of mitochondria was significantly less in the IR group mice than in the sham-operated mice (n=5 in each group). #P<0.05 versus sham.
Figure 2.
Figure 2.
Cytochrome c release into the cytosol of cardiomyocytes was increased by renal IR injury. (A) Representative image of Western blot analysis for cytochrome c in the cytosolic fractions. (B) Histogram showing the relative density of bands compared with α-tubulin (n=6 in each group). #P<0.05 versus sham.
Figure 3.
Figure 3.
Apoptosis of cardiomyocytes induced by renal IR injury. (A) Representative image of fluorescence immunohistochemistry for activated caspase-3 in the heart. Original magnification ×630. (B) Representative image of Western blot analysis for activated caspase-3 in whole tissue lysates. Original magnification ×400. (C) Histogram showing the relative density of bands compared with α-tubulin (n=4–6 in each group). #P<0.05 versus sham. *P<0.05 versus 24 h.
Figure 4.
Figure 4.
Mitochondrial dynamics regulating proteins in the heart 24 h after renal IR injury. (A) Amounts of each protein in mitochondrial fraction were evaluated using Western blot analysis. Histogram shows the relative density of bands compared with VDAC (n=4–6 in each group). #P<0.05 versus sham. (B) Amounts of each protein in whole tissue lysate were evaluated using Western blot analysis. Histogram shows the relative density of bands compared with α-tubulin (n=4–6 in each group).
Figure 5.
Figure 5.
Effects of Drp1 inhibitor mdivi-1 on renal function in mouse renal IR injury. (A) BUN and (B) plasma creatinine (Cre) concentration of each group (n=7 per group).
Figure 6.
Figure 6.
Effects of Drp1 inhibitor mdivi-1 on mitochondria of the heart in mouse renal IR injury. (A) Mitochondrial fragmentation was reduced by mdivi-1 treatment (n=5 per group). #P<0.05 versus sham. *P<0.05 versus IR. (B) Drp1 expression in the mitochondria fraction was reduced by mdivi-1 treatment (n=8–10 per group). #P<0.05 versus sham. *P<0.05 versus IR. (C) Cytochrome c release into the cytosolic fraction was suppressed by mdivi-1 treatment (n=6 per group). #P<0.05 versus sham. *P<0.05 versus IR.
Figure 7.
Figure 7.
Effects of Drp1 inhibitor mdivi-1 on the heart in mouse renal IR injury. (A) Apoptosis evaluated by Western blot analysis for activated caspase-3 was reduced by mdivi-1 treatment (n=6 per group). #P<0.05 versus sham. *P<0.05 versus IR 72 h. (B) Quantitative analysis of the fractional shortenings (FS) showed the protection of mdivi-1 (n=4–6 per group). #P<0.05 versus sham. *P<0.05 versus IR 72 h.
Figure 8.
Figure 8.
Effects of delayed mdivi-1 treatment on renal function in mouse renal IR injury. (A) BUN and (B) plasma creatinine (Cre) concentration of each group (n=7 per group).
Figure 9.
Figure 9.
Effects of delayed mdivi-1 treatment on mitochondria of the heart in mouse renal IR injury. (A) Mitochondrial fragmentation was reduced by mdivi-1 treatment (n=5 per group). #P<0.05 versus sham. *P<0.05 versus IR. (B) Drp1 expression in the mitochondria fraction was reduced by mdivi-1 treatment (n=8–10 per group). #P<0.05 versus sham. *P<0.05 versus IR.
Figure 10.
Figure 10.
Effects of delayed mdivi-1 treatment on the heart in mouse renal IR injury. (A) Apoptosis evaluated by Western blot analysis for activated caspase-3 was reduced by mdivi-1 treatment (n=6 per group). #P<0.05 versus sham. *P<0.05 versus IR 72 h. (B) Quantitative analysis of the fractional shortenings (FS) showed the protection of mdivi-1 (n=4–6 per group). #P<0.05 versus sham. *P<0.05 versus IR 72 h.

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