Histopathology and apoptosis in an animal model of reversible renal injury

Shuvy, Mony; Nyska, Abraham; Beeri, Rоnen; Abedat, Suzan; Gal-Moscovici, Anca; Rajamannan, Nalini M.; Lotan, Chaim

doi:10.1016/j.etp.2010.02.002

Cited by 41 publications

(29 citation statements)

References 14 publications

(14 reference statements)

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“…In another report, it has been shown that, in an adenine-loaded rat, which is widely used as a model for renal failure, cessation of the adenine diet led to the reversal of renal damage (Shuvy et al, 2011). In the present study, in DOCA rats with established renal injury, withdrawal of The Effect of CS-3150 on Renal Injury in DOCA Rats DOCA administration itself reversed renal injury.…”

Section: Induction Of Urinary Nasupporting

confidence: 47%

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

Arai

Morikawa

Ubukata

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury.

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Section: Induction Of Urinary Nasupporting

confidence: 47%

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

Arai

Morikawa

Ubukata

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…The renal toxicity of orally absorbed adenine is due to the formation of crystals that damage the nephrons. Indeed, adenine is metabolized to 2,8-dihydroxyadenine, which precipitates and forms tubular crystals that damage the renal tubules [11]. It is well known that 2,8-dihydroxyadenine exhibits a pH-dependent solubility in aqueous medium [35].…”

Section: Discussionmentioning

confidence: 99%

“…Supplementation with adenine in the diet induces kidney fibrosis, increased blood urea nitrogen and plasma creatinine [8] associated with an enhanced oxidative stress [10]. Adenine is metabolized to 2,8-dihydroxyadenine, which precipitates and forms tubular crystals that damage the kidney tissues [11]. Adenine can also be metabolized by xanthine oxidase into uric acid that can also precipitate in renal tubules.…”

Section: Introductionmentioning

confidence: 99%

Adenine Rich Diet Is Not a Surrogate of 5/6 Nephrectomy in Rabbits

Florens

Lemoine

Pelletier

et al. 2017

Nephron

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Background: Animal models are important tools needed to understand the mechanisms underlying the progression of renal disease and to implement new therapeutic approaches. A non-surgical model of chronic kidney disease (CKD) developed by chemical nephrectomy using an adenine-enriched diet has been shown to be a robust model to induce kidney failure in mice and rats. The purpose of this study was to implement an adenine diet to induce CKD in rabbits. Methods: Male New Zealand rabbits were fed for 4 weeks with a diet containing 0.75% (w/w) adenine, and renal function was assessed by measuring plasma urea and creatinine concentrations. The glomerular filtration rate (GFR) was measured using the plasmatic clearance of Iohexol. Kidney histology was performed with haematoxylin erythrosine saffron and Sirius red staining. Results: In contrast to what was observed in rodents, adenine diet failed to induce kidney failure in rabbits as is evident in the plasma concentrations of creatinine and urea and the direct measurement of GFR or histopathological studies. Conclusion: Adenine diet is not a surrogate of subtotal nephrectomy to induce kidney failure in rabbits. Several interspecies differences in metabolism and renal physiology could account for this observation.

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“…Adenine causes crystal precipitates in renal tubules and forms 2,8-dihydroxyadenine aggregates. Adenine alone causes renal failure due to interstitial nephritis (32). Clinically, chronic long-term RF in patients results in abnormal phosphate metabolism.…”

Section: Animal Modelmentioning

confidence: 99%

Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

Shuvy

Abedat

Beeri

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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failure is associated with aortic valve calcification. Using our rat model of uremiainduced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n ϭ 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n ϭ 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosisrelated genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.growth arrest-specific 6; uremia CARDIOVASCULAR CALCIFICATION is one of the highest causes of morbidities and mortalities in patients with end-stage renal disease. These patients develop aortic valve calcification (AVC) and coronary calcification at an accelerated rate. Associated with this cardiovascular calcification are increased rates of myocardial infarctions and valvular heart disease. The pathogenesis of AVC in renal failure (RF) is not fully elucidated. It has been suggested that the process involves active osteoblast transformation of valve tissue, which results in increased formation of bone matrix (4, 25). Most of the data regarding the pathogenesis of AVC were obtained from animal models based on various components of the metabolic syndrome, emphasizing the role of atherogenesis in AVC (26, 37). In patients with RF, AVC and aortic stenosis are common and progress especially rapidly (18). The prevalence and extent of AVC in this population is poorly explained by traditional cardiovascular risk factors; abnormalities of mineral metabolism are likely to contribute to its development and progression. Current models of RF and accelerated calcification have demonstrated that calcium phosphate metabolism is critical for disease development (13), and inhibitors of calcification (fetuin A) are important in its prevention...

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Histopathology and apoptosis in an animal model of reversible renal injury

Cited by 41 publications

References 14 publications

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

Adenine Rich Diet Is Not a Surrogate of 5/6 Nephrectomy in Rabbits

Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

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