First Indications Demonstrating the Preventive Effects of NZ-419, a Novel Intrinsic Antioxidant, on the Initiation and/or Progression of Chronic Renal Failure in Rats

Abstract

Although the number of patients with end-stage renal disease (ESRD) has increased rapidly over the last three decades and, prior to the advent of dialysis, some treatments including dietary control, drug therapy with a spherical carbonaceous absorbent, and anti-hypertensive drugs including ACEIs (angiotensin converting enzyme inhibitors) and ARBs (angiotensin receptor blockades) have shown some inhibition of the progression of chronic kidney disease (CKD) and chronic renal failure (CRF), these treatments are still not effective enough to curtail this increase. Therefore, the development of new effective drugs preventing the progression of CKD and CRF is still an urgent requirement. In the present article, we show the first indication that NZ-419 could be such a candidate.NZ-419 (5-hydroxy-1-methylimidazolidine-2,4-dione) ( Fig. 1) is a newly recognized intrinsic antioxidant, 1-8) a creatinine (Cr) metabolite, which was first isolated from inflamed skin inoculated with vaccinia virus 1) and subsequently from the urine of patients with CRF.2) The concentration of NZ-419 increases in the sera of mammals with CRF. 9)Both animal models and patients with CRF have been shown to be under more oxidative stress than corresponding normal animals and subjects, 6,7) and, in those studies, the level of methylguanidine (MG), which is a product of Cr with a hydroxyl radical, and the MG/Cr molar ratio in serum have been recognized to be useful as markers of oxidative stress in vivo 4,5,[9][10][11][12][13] in addition to conventional markers such as 8-hydroxyguanine, 14) 8-hydroxy deoxyguanosine, 14,15) and so on.The importance of oxidative stress in renal failure development has also been shown in different ways when more than two intrinsic anti-oxidant systems are inhibited, renal failure is induced. Acute renal failure (ARF) has been induced by vitamin E deficiency and glutathione (GSH) depletion in rats: hydroxyl radicals and lipid peroxide have been indicated to play important roles in renal failure formation. 16)In drug-induced ARF models, such as glycerol-induced ARF, a role of hydroxyl radicals in its initiation has been suggested, and the hydroxyl radical scavenger dimethylthiourea (DMTU) inhibited the development of ARF. 17)Also, in CRF models, some antioxidants which can scavenge hydroxyl radicals, such as tannins in plants, have been shown to inhibit the progression of CRF in several models, [18][19][20] together with inhibiting the increase in the MG level and MG/Cr ratio in serum and urine. The role of active oxygen in the progression of another CRF, murine lupus nephritis, has been shown, because DMTU inhibited the progression. 21)Therefore, safe antioxidants have been proposed to be candidates for anti-CRF agents, although hydroxyl radical scavengers with some side effects such as DMTU and dimethyl sulfoxide (DMSO) might not be suitable.Since the concentration of endogenous NZ-419 in sera increases by CRF 9) and NZ-419 has anti-oxidant activities, 7,8) at least hydroxyl radical scavenging activity, we hypothesize...

Treatment with NZ-419 (5-Hydroxy-1-methylimidazoline-2,4-dione), a Novel Intrinsic Antioxidant, against the Progression of Chronic Kidney Disease at Stages 3 and 4 in Rats

“…1) Stages of CRF patients are shown to be 3, 4, or 5: eGFR of these are 30-59, 15-29, or Ͻ15 ml/min/1.73 cm 3 , respectively. Since the clinical eGFR 0 has been shown to be ca.…”

“…1) In our previous paper, 3) we reported for the first time that an intrinsic antioxidant compound could prevent the initiation and/or progression of CRF: the compound investigated was NZ-419 (5-hydroxy-1-methylimidazolidine-2,4-dione, 5-hydroxy-1-methylhydantoin: HMH, CAS: 84210-26-4), [4][5][6][7][8][9] a creatinine (Cr) metabolite that prevented the initiation and/or progression of adenine-induced CRF. We chose CRF or CKD at stages equivalent to human stages 3, 4 and 5, where hydroxyl radicals are over-produced, 2,10) as one of the targets aims, 3,11,12) because NZ-419 had been shown to be a hydroxyl radical scavenger. 11,12) Meanwhile, since there is a hypothesis that oxidative stress might be a common key factor in the progression of CRF induced by several different causes, antioxidants might inhibit the progression of CRF regardless of its causes.…”

“…11,12) Meanwhile, since there is a hypothesis that oxidative stress might be a common key factor in the progression of CRF induced by several different causes, antioxidants might inhibit the progression of CRF regardless of its causes. 3) In order to assess whether NZ-419 could be used as a common treatment for CRF at CKD stages equivalent to human ones, 3, 4 and 5, its effect on CRF with other causes must be also investigated. Since adenine-induced CRF rats 13,14) have been shown to be a tubular lesion model, (as a glomerular lesion model) an additional model of 5/6 nephrectomized rats 15) was used together with the adenine-loaded rats in this study.…”

“…[20][21][22] In our previous paper, 3) we reported that NZ-419 could be one such safe candidate because crucial side effects were not observed at doses less than 1000 mg/kg/d.…”

The influence of mutant lactobacilli on serum creatinine and urea nitrogen concentrations and renal pathology in 5/6 nephrectomized rats

“…However, in recent years, many studies have shown that their metabolites are involved in the progression of kidney disease. Creatinine is converted to creatinine hydroxide in the presence of free radicals, 13 eventually generating methylguanidine which is more toxic, 14 which increases the expression of TGF-b1, CTGF and FN in renal tubular epithelial cells and exacerbates renal tubular interstitial fibrosis. 15 In this way, creatinine indirectly promotes fibrosis.…”