Nitrite-Derived Nitric Oxide Protects the Rat Kidney against Ischemia/Reperfusion Injury In Vivo: Role for Xanthine Oxidoreductase
Abstract
In normal conditions, nitric oxide (NO) is oxidized to the anion nitrite, but in hypoxia, this nitrite may be reduced back to NO by the nitrite reductase action of deoxygenated hemoglobin, acidic disproportionation, or xanthine oxidoreductase (XOR). Herein, is investigated the effects of topical sodium nitrite administration in a rat model of renal ischemia/reperfusion (I/R) injury. Rats were subjected to 60 min of bilateral renal ischemia and 6 h of reperfusion in the absence or presence of sodium nitrite (30 nmol) administered topically 1 min before reperfusion. Serum creatinine, serum aspartate aminotransferase, creatinine clearance, fractional excretion of Na(+), and plasma nitrite/nitrate concentrations were measured. The nitrite-derived NO-generating capacity of renal tissue was determined under acidic and hypoxic conditions by ozone chemiluminescence in homogenates of kidneys that were subjected to sham, ischemia-only, and I/R conditions. Nitrite significantly attenuated renal dysfunction and injury, an effect that was abolished by previous treatment of rats with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide (2.5 mumol intravenously 5 min before ischemia and 50 nmol topically 6 min before reperfusion). Renal tissue homogenates produced significant amounts of NO from nitrite, an effect that was attenuated significantly by the xanthine oxidoreductase inhibitor allopurinol. Taken together, these findings demonstrate that topically administered sodium nitrite protects the rat kidney against I/R injury and dysfunction in vivo via the generation, in part, of xanthine oxidoreductase-catalyzed NO production. These observations suggest that nitrite therapy might prove beneficial in protecting kidney function and integrity during periods of I/R such as those encountered in renal transplantation.
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Nitrite is a dietary constituent that protects the heart against I/R injury in many animal models during both ischemia and preconditioning stage.
“Nitrite is a dietary constituent that protects the heart against I/R injury in many animal models during both ischemia and preconditioning stage [186,187,188,189,190,191,192].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [187]
Nitrite-mediated cytoprotection is mediated by NO production from the molybdenum-containing enzyme XOR and to some extent SO.
“Numerous studies have suggested that nitrite-mediated cytoprotection is mediated by NO production from the molybdenum containing enzyme XOR [8, 39, 86, 118, 127] and to some extent SO [39] as well.”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [127]
NO production from nitrite in kidney homogenates was largely attenuated by allopurinol.
“and NO production from nitrite in kidney homogenates was largely attenuated by allopurinol [127].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [127]
Topical administration of nitrite was protective against renal IR injury in an in vivo rat model.
“In addition, topical administration of nitrite was found to be protective against renal IR injury in an in vivo rat model”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [127]
Nitrite administration reduces skeletal muscle, renal, and liver injury after ischemia.
“nitrite administration reduces skeletal muscle (188), renal (125, 179), and liver (46, 154, 169) injury after ischemia.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [179]
Some therapeutic effects of nitrite are sensitive to xanthine oxidoreductase inhibition.
“some therapeutic effects of nitrite are sensitive to xanthine oxidoreductase inhibition [73, 74]”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [73]
Nitrite reduction to NO involves mechanisms including pH-dependent reduction in the stomach, reduction by xanthine oxidase, deoxyhemoglobin, myoglobin, cytochrome P450, and enzymes of the mitochondrial respiratory chain.
“The mechanisms involved in nitrite reduction to NO include pH-dependent reduction in the stomach [9,10] or reduction by xanthine oxidase [11,12], deoxyhemoglobin [13], myoglobin [14,15], cytochrome P450 [16], and enzymes of the mitochondrial respiratory chain [17].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [11]
Nitrite or nitrate have been associated with beneficial effects including protection against ischemia-reperfusion injury, vasorelaxant properties, pulmonary vasodilator effects, and antihypertensive effects in experimental and clinical studies.
“relevant biological effects were associated with nitrite or nitrate, including beneficial effects against ischemia-reperfusion injury [11,18,19], vasorelaxant properties [20], pulmonary vasodilator effects [21][22][23], and antihypertensive effects in experimental [24][25][26][27] and in clinical studies [28][29][30].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [11]
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References 50 · Cited by 226
- Authors
- Tripatara, P., Patel, N. S. A., Webb, A., Rathod, K., Lecomte, F. M. J., Mazzon, E., Cuzzocrea, S., Yaqoob, M. M., Ahluwalia, A., & Thiemermann, C.
- Affiliations
- Queen Mary University of London (GB)
- ORCID
- Venue
- Journal of the American Society of Nephrology
- Published
- 2007-02
- Volume
- 18
- Issue
- 2
- Pages
- 570-580
- ISSN
- 1046-6673 (ISSN-L)
- OpenAlex
- W2165949229
- Cited by
- 226
- References
- 50
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 8 · 2017: 15 · 2016: 12 · 2015: 24 · 2014: 17 · 2013: 24 · 2012: 17
- FWCI
- 13.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- nitrite, nitric oxide, renal ischemia-reperfusion injury, sodium nitrite, xanthine oxidoreductase, allopurinol, renal protection, nitric oxide scavengers, renal dysfunction, kidney transplantation
- MeSH terms
- Animals, Disease Models, Animal, Kidney, Male, Nitrates, Nitrites, Renal Circulation, Tyrosine, Xanthine Dehydrogenase, Reperfusion Injury, Rats, Wistar, Rats, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III
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