Severe hyperparathyroidism with bone abnormalities and metastatic calcification in rats with adenine-induced uraemia

Tamagaki, Keiichi; Yuan, Qunsheng; Ohkawa, Hiroyuki; Imazeki, Ikuo; Moriguchi, Yoshiyuki; Imai, Nobuo; Sasaki, Susumu; Takeda, Kazuo; Fukagawa, Masafumi

doi:10.1093/ndt/gfi273

Cited by 90 publications

(100 citation statements)

References 17 publications

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“…Thus, the analysis of serum calcium and inorganic phosphate indicated their abnormalities in this model, as shown before, 23,30) with decreasing and increasing levels, respectively. The NZ-419-administered groups maintained almost normal levels, and this inhibition was nearly complete.…”

Section: Discussionsupporting

confidence: 77%

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

Ienaga

Mikami

Yokozawa

2009

Biological & Pharmaceutical Bulletin

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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...

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Section: Discussionsupporting

confidence: 77%

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

Ienaga

Mikami

Yokozawa

2009

Biological & Pharmaceutical Bulletin

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“…19,20,42,43 Our animal model, the LDLR Ϫ/Ϫ mouse fed a high-fat diet, is an animal model of atherosclerosis, and because of hyperlipidemia, obesity, and insulin resistance, the metabolic syndrome. In this animal model, VC develops in aortic atherosclerotic neointima 19,26 associated with expression of an osteoblastic differentiation program directed by BMP-2 and MSX2 along with the transcriptional effects of the osteoblast transcription factor RUNX2.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Mathew¹,

Tustison²,

Sugatani³

et al. 2008

Journal of the American Society of Nephrology

209

171

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Hyperphosphatemia and vascular calcification have emerged as cardiovascular risk factors among those with chronic kidney disease. This study examined the mechanism by which phosphorous stimulates vascular calcification, as well as how controlling hyperphosphatemia affects established calcification. In primary cultures of vascular smooth muscle cells derived from atherosclerotic human aortas, activation of osteoblastic events, including increased expression of bone morphogenetic protein 2 (BMP-2) and the transcription factor RUNX2, which normally play roles in skeletal morphogenesis, was observed. These changes, however, did not lead to matrix mineralization until the phosphorus concentration of the media was increased; phosphorus stimulated expression of osterix, a second critical osteoblast transcription factor. Knockdown of osterix with small interference RNA (siRNA) or antagonism of BMP-2 with noggin prevented matrix mineralization in vitro. Similarly, vascular BMP-2 and RUNX2 were upregulated in atherosclerotic mice, but significant mineralization occurred only after the induction of renal dysfunction, which led to hyperphosphatemia and increased aortic expression of osterix. Administration of oral phosphate binders or intraperitoneal BMP-7 decreased expression of osterix and aortic mineralization. It is concluded that, in chronic kidney disease, hyperphosphatemia stimulates an osteoblastic transcriptional program in the vasculature, which is mediated by osterix activation in cells of the vascular tunica media and neointima. Chronic kidney disease (CKD) is a fatal illness, and cardiovascular complications are the major causes of morbidity and mortality. 1,2 The causes of the excess cardiovascular mortality associated with CKD are unknown, because the role of the standard risk factors associated with cardiovascular mortality do not account for the increased risk in CKD. 2 There is strong epidemiologic evidence that serum phosphorus is an independent risk factor for cardiovascular events and mortality in CKD. 3,4 The serum phosphorus has been linked to another cardiovascular risk factor, vascular calcification (VC), 3,5,6 an important cause of vascular stiffness in CKD leading to increased pulse wave velocity, increased cardiac work, left ventricular hypertrophy, and decreased coronary artery blood flow. 6 -8 Phosphorus has been further implicated as a cause of VC through studies in vitro that have demonstrated that it induces phenotypic changes in vascular smooth muscle cells (VSMC) by increasing gene transcription of proteins involved in osteoblast function-bone formation 9 and stimulating matrix mineralization. 10 -12 In the uremic calcifying environment, expression of the contractile proteins of VSMC, such as ␣-smooth muscle actin, SM22,

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“…It has been demonstrated that mice have a relatively higher sensitivity to adenine-induced toxicity than rats. Rats tolerate dietary levels of adenine at 0.75% for prolonged periods (8 weeks or more) [9,11,19,22] Figure 3. Histology of sliced/ H&E stained kidneys from selected groups in murine adenine-induced kidney insufficiency studies.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, concurrent active vitamin D supplementation prescribed due to a reduced ability of the kidney to convert vitamin precursors to active vitamin D further exacerbates phosphate absorption [6,7]. Previously, the rat models including the 5/6 nephrectomy and adenineinduced kidney insufficiency rat model have been extensively used for pre-clinical testing in the development of therapies for chronic kidney disease [8][9][10]. The rat adenine-induced kidney insufficiency model is a less invasive refinement over the 5/6 nephrectomy surgical renal insufficiency model [11,12], and was found useful in the development of sevelamer hydrochloride (Sev HCl) as an oral therapy for treatment of hyperphosphatemia [10].…”

Section: Introductionmentioning

confidence: 99%

“…The rat adenine-induced kidney insufficiency model is a less invasive refinement over the 5/6 nephrectomy surgical renal insufficiency model [11,12], and was found useful in the development of sevelamer hydrochloride (Sev HCl) as an oral therapy for treatment of hyperphosphatemia [10]. Rats fed 0.75% dietary adenine for two weeks developed increased blood phosphate, FGF23, and blood urea nitrogen due to renal insufficiency, appearing sufficient to model human CKD [8,9,11].…”

Section: Introductionmentioning

confidence: 99%

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Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

Bobeck¹,

Piccione²,

Bishop³

et al. 2017

Nephrol Renal Dis

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Hyperphosphatemia in chronic kidney disease (CKD) patients is a risk factor for cardiovascular events, progressive kidney failure, and mortality. Improved therapeutic interventions to control hyperphosphatemia depend greatly on robust animal models that recapitulate the CKD disease process. Murine-based models of CKD as compared to rat models present significant advantages due to available genetic knockout lines that permit mechanistic dissection of CKD etiologies. The rat adenine model of renal failure has been extensively studied, and studies are now emerging describing adenine-induced renal failure in murine models. However, these newly developed murine models have not fully described the responses to calcitriol and phosphate binders, and the reported effects of adenine on serum phosphate is often lacking in murine models. Therefore, the objectives of this study were: 1) To induce hyperphosphatemia in mice using adenine with minimal mortality, and 2) Report the influence of calcitriol and phosphate binders on the disease process through measurement of serum phosphate and histology. In one approach, C57BL/6 male mice gavaged with 4 or 6 mg adenine/day, as compared to 0 mg adenine/day developed hyperphosphatemia, with low mortality. In a second approach, calcitriol exacerbated adenine-induced increases in serum phosphate at day 7 of adenine administration (p<0.05). Notably, adenine treated mice had 4-fold increased stomach weights vs. non-adenine treated mice (p<0.0001). The addition of a phosphate binder (experiment 3, sevelamer hydrochloride) was ineffective at preventing an adenine-induced increase in blood phosphate, a finding that likely resulted from adenine's inhibition of gastric emptying. We report the successful use of adenine to induce hyperphosphatemia, that the hyperphosphatemic status is exacerbated by calcitriol, and a limitation of the model for studying oral therapies for hyperphosphatemia.

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Severe hyperparathyroidism with bone abnormalities and metastatic calcification in rats with adenine-induced uraemia

Abstract: Uraemic rats made by adenine diet developed severe abnormalities of calcium metabolism in a relatively short period and therefore they may serve as a useful model for the analysis of parathyroid hyperplasia and vascular calcification in chronic renal failure.

Cited by 90 publications

References 17 publications

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

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

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

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