Inflammation and oxidative stress are known to be involved in the pathogenesis of chronic kidney disease in humans, and in chronic renal failure (CRF) in rats. The aim of this work was to study the role of inflammation and oxidative stress in adenine-induced CRF and the effect thereon of the purported nephroprotective agent gum arabic (GA). Rats were divided into four groups and treated for 4 weeks as follows: control, adenine in feed (0.75%, w/w), GA in drinking water (15%, w/v) and adenine+GA, as before. Urine, blood and kidneys were collected from the rats at the end of the treatment for analysis of conventional renal function tests (plasma creatinine and urea concentration). In addition, the concentrations of the pro-inflammatory cytokine TNF-α and the oxidative stress markers glutathione and superoxide dismutase, renal apoptosis, superoxide formation and DNA double strand break frequency, detected by immunohistochemistry for γ-H2AX, were measured. Adenine significantly increased the concentrations of urea and creatinine in plasma, significantly decreased the creatinine clearance and induced significant increases in the concentration of the measured inflammatory mediators. Further, it caused oxidative stress and DNA damage. Treatment with GA significantly ameliorated these actions. The mechanism of the reported salutary effect of GA in adenine-induced CRF is associated with mitigation of the adenine-induced inflammation and generation of free radicals.

STEM CELLS 2006;24: 1226 -1235

Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong antioxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine-induced CKD. Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue. Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase-associated lipocalin levels and raised urinary N-acetyl-b-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1b, IL-6 and TNF-a, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level. In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up-regulation of the transcription factor Nrf2.Chronic kidney disease (CKD) is a major and growing public health problem in both developed [1] and developing countries [2]. CKD is considered a key determinant of the poor health outcome of major non-communicable diseases [3] because of the high prevalence of morbidity and mortality associated with it, mainly due to cardiovascular dysfunction. Till now, there is no drug to improve kidney function in patients with CKD. The current therapeutic approaches to slow down its progression are limited to normalization of insulin, glucose and blood pressure [4]. Therefore, the development of novel therapies to either slow or reverse the deterioration in kidney function is highly needed. In particular, interesting for this are natural products with proven safety profiles.The pathophysiological basis of CKD and its complications include inflammation, oxidative stress and apoptosis [5]. These features consistently occur in human beings and animals. They are also major mediators of the disease, exerting similar effects in chronic renal failure models in rats [6,7]. Patients and laboratory animals with CKD have high plasma concentrations of inflammatory mediators (such as C-reactive protein, tumour necrosis factor and other cytokines) and several markers of nitrosative and oxidative stress [8,9]. Turmeric (Curcuma longa) is a popular Asian spice that has been utilized for...

Benfotiamine shows a direct antioxidant action. This effect of benfotiamine may be involved in the improvement of diabetic late complications, including peripheral neuropathy.

Epidemiological studies exploring the connection between hypertension and cancer demonstrate a higher cancer incidence, especially of kidney cancer, and a higher cancer mortality in hypertensive patients. Hormones elevated in hypertension, i.e., aldosterone and angiotensin II, which exert genotoxic effects in vitro, could contribute to carcinogenesis in hypertension. The present study was conducted to investigate the possible DNA-damaging effect of aldosterone receptor activation in vivo. Crl:CD (Sprague-Dawley) rats were treated for 6 wk with desoxycorticosterone acetate (DOCA) and salt to induce a mineralocorticoid-dependent hypertension. DOCA-salt treatment caused increased blood pressure (؉26 mmHg) compared to untreated rats, elevated markers of kidney failure (up to 62-fold for Kim-1), and the induction of several proinflammatory genes and proteins (up to 2.6-fold for tissue MCP-1). The mineralocorticoid receptor (MR) antagonist spironolactone (MR IC 50 24 nM) and the novel nonsteroidal antagonist BR-4628 (MR IC 50 28 nM) decreased these damage markers. DOCA-salt treatment also caused 8.8-fold increased structural DNA damage, determined with the comet assay, double-strand breaks (3.5-fold), detected immunohistochemically, and oxidative stress. Furthermore, the oxidatively modified mutagenic DNA base 7,8-dihydro-8-oxoguanine (8-oxodG), quantified by LC-MS/MS, was almost 2-fold higher in DOCA-salt-treated kidneys. Our results suggest a mutagenic potential of high mineralocorticoid levels, frequent in hypertensive individuals.-Schupp, N., Kolkhof, P., Queisser, N., Gärtner, S., Schmid, U., Kretschmer, A., Hartmann, E., Oli, R G., Schäfer, S., Stopper, H. Mineralocorticoid receptor-mediated DNA damage in kidneys of DOCA-salt hypertensive rats. FASEB J. 25, 968 -978 (2011). www.fasebj.org Key Words: 8-oxodG ⅐ double-strand breaks ⅐ hypertension ⅐ oxidative DNA damage ⅐ oxidative stressAldosterone is produced in the adrenal zona glomerulosa on stimulation by angiotensin II, potassium, or the adrenocorticotropic hormone. Classically, it regulates sodium excretion and thereby blood pressure homeostasis through mineralocorticoid receptor (MR) dependent, genomic effects in the distal nephron of the kidney. Together with angiotensin II, it is the major effector of the renin-angiotensin-aldosterone system. Recent studies suggest that 10 -15% of hypertensive individuals have an elevated aldosterone to renin ratio, a biochemical measure for hyperaldosteronism (1). The plasma concentration of aldosterone in these patients ranges from 0.5 to 6.3 nM, with patients suffering from congestive heart failure reaching 8 nM (2, 3). Studies demonstrating the effectiveness of MR antagonism in patients with resistant hypertension, also support the high prevalence (20%) of hyperaldosteronism in this population (1, 4). Aldosterone plays an important role in the pathophysiology of heart failure. Clinical trials examining the effect of combined angiotensin converting enzyme (ACE) inhibition and MR antagonism showed a reduction of mortalit...