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Peroxynitrite-induced protein nitration is responsible for renal mitochondrial damage in diabetic rat
1Department of Biochemistry, Hebei Medical University, 050017 Shijiazhuang, PR China.
Abstract:
Oxidative stress, especially mediated by peroxynitrite (ONOO-), plays a key role in diabetes. Mitochondria, as the generating source of ONOO-, may also be the major damaging target of ONOO-. Whether ONOO--induced protein nitration is responsible for renal mitochondrial damage in diabetes is not fully known. This study was aimed to clarify the relationship between nitration of entire mitochondrial proteins induced by ONOO- and the renal mitochondrial damage in diabetes. Sprague-Dawley male rats were injected ip with streptozotocin to induce diabetes. After 10 weeks, inducible nitric oxide synthase (iNOS) mRNA expression and protein content in renal cortex were detected. Distribution of nitrotyrosine (NT), a specific marker of ONOO-, in renal cortex and NT content in mitochondrial proteins were detected. The ultrastructure of glomerulus was observed. Aminoguanidine was used as a selective inhibitor of iNOS to reduce the derivation of ONOO-. In diabetic rat, increasing levels of iNOS mRNA and protein content, and NT content were observed, in accord with the pathological alterations of glomerulus. In aminoguanidine group, these alterations were attenuated significantly. In conclusion, ONOO- could induce entire mitochondrial proteins nitration, responsible for the damage of renal mitochondria in diabetes.
Insights
Peroxynitrite (ONOO-) causes kidney mitochondrial damage in diabetes by nitrating mitochondrial proteins. Inhibiting peroxynitrite formation with aminoguanidine attenuated these harmful effects in diabetic rats.
Area of Science:
- Biochemistry
- Pathology
- Nephrology
Background:
- Oxidative stress, particularly peroxynitrite (ONOO-), is implicated in diabetes.
- Mitochondria are both a source and a target of ONOO- damage.
- The role of ONOO--induced protein nitration in diabetic renal mitochondrial injury is unclear.
Purpose of the Study:
- To investigate the link between ONOO--induced nitration of mitochondrial proteins and renal mitochondrial damage in diabetes.
- To elucidate the mechanism of ONOO- mediated damage in diabetic nephropathy.
Main Methods:
- Streptozotocin-induced diabetes in Sprague-Dawley rats.
- Assessment of inducible nitric oxide synthase (iNOS) mRNA and protein.
- Detection of nitrotyrosine (NT) as a marker of ONOO-.
- Mitochondrial protein nitration analysis.
- Glomerular ultrastructural observation.
- Pharmacological inhibition of iNOS using aminoguanidine.
Main Results:
- Diabetic rats showed increased iNOS expression and NT levels in the renal cortex.
- Elevated NT content was found in mitochondrial proteins, correlating with glomerular damage.
- Aminoguanidine treatment significantly reduced iNOS, NT levels, and pathological alterations.
Conclusions:
- Peroxynitrite induces nitration of mitochondrial proteins, leading to renal mitochondrial damage in diabetes.
- Protein nitration by ONOO- is a key mechanism underlying diabetic nephropathy.
- Targeting iNOS and ONOO- formation may offer therapeutic strategies for diabetic kidney disease.
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