Dietary nitrite ameliorates renal injury in l-NAME-induced hypertensive rats

Nitric oxide (NO) has numerous important functions in the kidney, and long-term blockage of nitric oxide synthases in rats by l-NAME results in severe hypertension and progressive kidney damage. On the other hand, NO production seems to be low in patients with chronic kidney disease (CKD), and NO deficiency may play a role in CKD progression.In this review, we summarized the mechanisms of amelioration of renal injury induced by l-NAME treated rats by treatment of nitrite.First, we demonstrate whether orally-administrated nitrite-derived NO can shift to the circulation. When 3 mg/kg body weight Na15NO2 was orally administered to rats, an apparent EPR signal derived from Hb15NO (Az = 23.4 gauss) appeared in the blood, indicating that orally ingested nitrite can be a source of NO in vivo.Next, in order to clarify the capacity of nitrite to prevent renal disease, we administered low-dose nitrite (LDN: 0.1 mg of sodium nitrite in 1 L of drinking water), medium-dose nitrite (MDN: 1 mg sodium nitrite/L, which corresponds to the amount of nitrite ingested by vegetarians), or high-dose nitrite (HDN: 10 mg sodium nitrite/L) to rats simultaneously with l-NAME (1 g l-NAME/L) for 8 weeks, then examined the blood NO level as a hemoglobin–NO adduct (iron-nitrosyl-hemoglobin) using electron paramagnetic resonance spectroscopy, urinary protein excretion, and renal histological changes at the end of the experiment.It was found that oral administration of MDN and HDN but not LDN increased the blood iron-nitrosyl-hemoglobin concentration to the normal level, ameliorated the l-NAME-induced proteinuria, and reduced renal histological damage. The findings demonstrate that chronic administration of a mid-level dietary dose of nitrite restores the circulating iron-nitrosyl-hemoglobin levels reduced by l-NAME and that maintenance of the circulating iron-nitrosyl-hemoglobin level in a controlled range protects against l-NAME-induced renal injury.Taking these findings together, we propose that dietary supplementation of nitrite is a potentially useful nonpharmacological strategy for maintaining circulating NO level in order to prevent or slow the progression of renal disease.It had been believed that nitrite could result in intragastric formation of nitrosamines, which had been linked to esophageal and other gastrointestinal cancers. However, there is no positive association between the intake of nitrate or nitrite and gastric and pancreatic cancer by recent researches. Furthermore, nitrate-derived NO formation pathway is a possible mechanism for the hypotensive effect of vegetable- and fruit-rich diets, which may explain, at least in part, the mechanism of the Dietary Approach to Stop Hypertension (DASH) diet-induced hypotensive and organ-protective effects. Further research is needed to investigate the interaction between nitrite–nitrate intakes and human health.