Anat Cell Biol.  2017 Sep;50(3):200-206. 10.5115/acb.2017.50.3.200.

Spermidine is protective against kidney ischemia and reperfusion injury through inhibiting DNA nitration and PARP1 activation

• Kim J

• KMID: 2390481
• DOI: http://doi.org/10.5115/acb.2017.50.3.200

Abstract

Kidney ischemia and reperfusion injury (IRI) is associated with a high mortality rate, which is attributed to tubular oxidative and nitrative stresses; however, an effective approach to limit IRI remains elusive. Spermidine, a naturally occurring polyamine, protects yeast cells against aging through the inhibition of oxidative stress and necrosis. In the present study, spermidine supplementation markedly attenuated histological damage and kidney dysfunction during IRI. In addition, exogenous spermidine potently inhibited poly(ADP-ribose) polymerase 1 (PARP1) activation and DNA nitrative/oxidative stress following IRI. Conversely, inhibition of ornithine decarboxylase (ODC) via siRNA transfection in vivo significantly enhanced DNA nitration, PARP1 activation, and functional damage during IRI. Finally, in ODC knockdown kidneys, PARP1 inhibition attenuated histological and functional damage induced by IRI, but not DNA nitrative stress. In conclusion, these data suggest that spermidine protects kidneys against IRI through blocking DNA nitration and PARP1 activation and this finding provides a novel target for prevention of acute kidney injury including IRI.

Keyword

Spermidine; Poly(ADP-ribose) polymerase 1; Nitration; Ischemia and reperfusion injury; Ornithine decarboxylase

MeSH Terms

Acute Kidney Injury
Aging
DNA*
Ischemia*
Kidney*
Mortality
Necrosis
Ornithine Decarboxylase
Oxidative Stress
Poly(ADP-ribose) Polymerases
Reperfusion Injury*
Reperfusion*
RNA, Small Interfering
Spermidine*
Transfection
Yeasts
DNA
Ornithine Decarboxylase
Poly(ADP-ribose) Polymerases
RNA, Small Interfering
Spermidine

Figure

• 

  Fig. 1 Exogenous spermidine attenuates tubular damage and kidney dysfunction during ischemia and reperfusion injury (IRI). Mice were subjected to 30 minutes of bilateral kidney ischemia or sham operation followed by 6 hours or 24 hours of reperfusion. Spermidine (10 mg/kg body weight) or vehicle was administered at 24 hours and 1 hour before ischemia. n=9 mice in each group. (A) Tubular damage in the outer medulla represented by periodic acid-Schiff (PAS) stain in kidney sections of mice. Scale bars=50 µm. (B) Tubular injury score measured in PAS-stained kidney sections. (C) Plasma creatinine concentration. ***P<0.001 vs. vehicle.

• 

  Fig. 2 Exogenous spermidine reduces poly(ADP-ribose) polymerase 1 (PARP1) activation and DNA nitration during ischemia and reperfusion injury (IRI). Mice were subjected to 30 minutes of bilateral kidney ischemia or sham operation followed by 6 or 24 hours of reperfusion. Spermidine (10 mg/kg body weight) or vehicle was administered at 24 hours and 1 hour before ischemia. n=9 mice in each group. (A) PARP1 activity in kidneys. (B) DNA nitration represented by 8-nitroguanine in kidneys. (C) DNA oxidation represented by 8-hydroxy-2′-deoxyguanosine concentration in kidneys. *P<0.05, **P<0.01 and ***P<0.001 vs. vehicle.

• 

  Fig. 3 Ornithine decarboxylase (ODC) siRNA exacervates the consequences of ischemia and reperfusion injury (IRI). Mice were subjected to 30 minutes of bilateral kidney ischemia or sham operation followed by 6 hours or 24 hours of reperfusion. ODC siRNA or control siRNA was injected at 48 hours and 24 hours before ischemia. n=9 mice in each group. (A) DNA nitration represented by 8-nitroguanine in kidneys. (B) Poly(ADP-ribose) polymerase 1 (PARP1) activity in kidneys. (C) Tubular damage in the outer medulla represented by periodic acid-Schiff (PAS) stain in kidney sections of mice. Scale bars=50 µm. (D) Tubular injury score measured in PAS-stained kidney sections. (E) Plasma creatinine concentration. ***P<0.001 vs. siControl.

• 

  Fig. 4 Exogenous spermidine attenuates tubular damage and kidney dysfunction after ischemia and reperfusion injury (IRI) through inhibiting DNA nitration and poly(ADP-ribose) polymerase 1 (PARP1) activation. Mice were subjected to 30 minutes of bilateral kidney ischemia or sham operation followed by 24 hours of reperfusion. Ornithine decarboxylase (ODC) siRNA was injected at 48 and 24 hours before ischemia. Spermidine (10 mg/kg body weight), PJ34 (10 mg/kg body weight), or vehicle was administered at 24 hours and 1 hour before ischemia. n=9 mice in each group. (A) DNA nitration represented by 8-nitroguanine in kidneys. (B) PARP1 activity in kidneys. (C) Plasma creatinine concentration. (D) Tubular damage in the outer medulla represented by periodic acid-Schiff (PAS) stain in kidney sections of mice. Scale bars=50 µm. (E) Tubular injury score measured in PAS-stained kidney sections. ***P<0.001 vs. vehicle, ##P<0.01, ###P<0.001 vs. PJ34.

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