Cristino Cruz

Protective effects of apocynin against cisplatin-induced oxidative stress and nephrotoxicity.

Cis-diamminedichloroplatinum (II) (cisplatin) is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors; however, nephrotoxicity has restricted its clinical use. Several studies have shown that reactive oxygen species are involved in cisplatin-induced nephrotoxicity, including hydrogen peroxide, hydroxyl radical and superoxide anion (O(2)(-)). The source of O(2)(-) in cisplatin-induced renal damage has not been established. The aim of this study was to investigate if NADPH oxidase is involved in cisplatin-induced nephrotoxicity using apocynin, a widely used NADPH oxidase inhibitor. Rats were studied 3 days after a single injection of cisplatin (7.5mg/kg, i.p.). Apocynin was given in the drinking water (2g/L) 7 days before and 3 days after cisplatin injection. Apocynin treatment was able to ameliorate the renal histological damage and the increase in blood urea nitrogen, serum creatinine, and urinary excretion of total protein, N-acetyl-beta-d-glucosaminidase and glutathione-S-transferase induced by cisplatin. In addition, the protective effect of apocynin was associated with the amelioration of cisplatin-induced oxidative and nitrosative stress. Our data suggest that O(2)(-) derived from NADPH oxidase triggers some of the side effects due to cisplatin administration.

Renoprotection by α-mangostin is related to the attenuation in renal oxidative/nitrosative stress induced by cisplatin nephrotoxicity

Cisplatin (CDDP) is a chemotherapeutic agent that produces nephrotoxicity associated with oxidative/nitrosative stress. α-Mangostin (α-M) is a xanthone extracted from mangosteen with antioxidant and anti-inflammatory properties. The purpose of this study was to evaluate the renoprotective effect of α-M on the CDDP-induced nephrotoxicity. α-M was administered (12.5 mg/kg/day, i.g.) for 10 days (7 days before and 3 days after CDDP injection). On day 7, rats were treated with a single injection of CDDP (7.5 mg/Kg, i.p.); 3 days after the rats were killed. α-M attenuated renal dysfunction, structural damage, oxidative/nitrosative stress, decrease in catalase expression and increase in mRNA levels of tumour necrosis factor alpha and transforming growth factor beta. In conclusion the renoprotective effect of α-M on CDDP-induced nephrotoxicity was associated with the attenuation in oxidative/nitrosative stress and inflammatory and fibrotic markers and preservation of catalase activity.

Recovery from ischemic acute kidney injury by spironolactone administration

BACKGROUND Prophylactic mineralocorticoid receptor (MR) antagonism with spironolactone (Sp) in rats completely prevents renal damage induced by ischemia. Because acute renal ischemia cannot typically be predicted, this study was designed to investigate whether Sp could prevent renal injury after an ischemic/reperfusion insult. METHODS Six groups of male Wistar rats were studied: rats that received a sham abdominal operation (S); rats that underwent 20 min of ischemia and reperfusion for 24 h (I/R) and four groups of rats treated with Sp (20 mg/kg) 0, 3, 6 or 9 h after ischemia. RESULTS As expected, I/R resulted in renal dysfunction characterized by a fall in renal blood flow and glomerular filtration rate and severe tubular injury which was confirmed by a significant increase in tubular damage biomarkers including kidney injury molecule-1, heat shock protein 72 and urinary protein excretion. The renal injury induced by I/R was in part due to Rho-kinase, endothelin and angiotensin II type 1 receptor upregulation. Interestingly, Sp administration at 0 and 3 h after ischemia completely reversed and prevented the damage induced by I/R. The protection induced by Sp given 6 h after ischemia was partial, but no protection was observed by administering Sp 9 h after ischemia. CONCLUSION Our results show that MR antagonism administered, either immediately or 3 h after I/R, effectively prevented ischemic acute renal injury, indicating that spironolactone is a promising agent for preventing acute kidney injury once an ischemic insult has occurred.

Adrenalectomy prevents renal ischemia-reperfusion injury

Spironolactone treatment prevents renal damage induced by ischemia-reperfusion (I/R), suggesting that renoprotection conferred by spironolactone is mediated by mineralocorticoid receptor (MR) blockade. It is possible, however, that this effect is due to other mechanisms. Therefore, this study evaluated whether adrenalectomy prevented renal damage induced by I/R. Three groups of Wistar rats were studied: 1) a group subjected to a sham surgery, 2) a group subjected to bilateral I/R, and 3) a group of rats in which adrenal glands were removed 3 days before induction of I/R. As expected, I/R resulted in renal dysfunction and severe tubular injury that was associated with a significant increase in tubular damage markers. In contrast, there was no renal dysfunction or tubular injury in rats that were adrenalectomized before I/R. These effects were demonstrated by normalization of glomerular filtration rate, markers of oxidative stress, and tubular injury markers in adrenalectomized rats. The renoprotection observed was associated with the reestablishment of nitric oxide metabolites, increased endothelial nitric oxide synthase expression and its activating phosphorylation, as well as normalization of Rho-kinase expression and ET(A) mRNA levels. Our results show that aldosterone plays a central role in the pathogenesis of renal damage induced by I/R and that MR blockade may be a promising strategy that opens a new therapeutic option for preventing acute renal injury.

Effects of losartan pretreatment in an experimental model of ischemic acute kidney injury

Background/Aims: Contributions to the understanding of acute renal failure (ARF) pathogenesis have not been translated into an effective clinical therapy. We studied the effects of pretreatment with the angiotensin II type 1 (AT1) receptor blocker, losartan, on renal function, tissue injury, inflammatory response and serum aldosterone levels in a model of ischemic ARF. Methods: Rats underwent unilateral renal ischemia followed by 24 h of reperfusion (IR), and were pretreated or not with 8 (IRL8) or 80 (IRL80) mg/kg/day of losartan for 3 days. Results: IR kidneys showed marked renal dysfunction, epithelial damage, capillary congestion, increased myeloperoxidase (MPO) activity and increased TNF-α, IL1-β and IL-6 mRNA levels. IRL80 kidneys showed protection against dysfunction and tissue injury, associated with normal MPO activity and cytokine mRNA levels. The lower dose was not able to achieve the same degree of functional renoprotection and could not prevent an increase of MPO or proinflammatory cytokine mRNA levels. The high losartan dose completely prevented an increase of serum aldosterone levels induced by IR. Conclusion: Renoprotection of the high losartan dose would be mainly mediated by its anti-inflammatory actions. Our results show a potential pathophysiological role of AT1 activation in promoting renal dysfunction, structural injury, inflammation and aldosterone elevation after IR injury.

Preventive effect of tert-butylhydroquinone on cisplatin-induced nephrotoxicity in rats

Cis-diamminedichloroplatinum II (CDDP)-induced nephrotoxicity is associated with the overproduction of reactive oxygen species. tert-Butylhydroquinone (tBHQ) is a compound widely used as food antioxidant. The purpose of this study was to investigate the ability of tBHQ to prevent the nephrotoxic effect of CDDP in rats as well as the mechanisms involved. Thirty-six Wistar rats divided in the following groups were used: control, tBHQ (12.5mg/kg), CDDP (7.5mg/kg) and tBHQ+CDDP. Twenty-four h urine was collected at the beginning and at the end of the experiment and the rats were sacrificed 72h after CDDP-administration. Histological studies were performed and markers of renal function and oxidative/nitrosative stress were measured. In addition, the activity of the following antioxidant enzymes was measured: glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione reductase (GR) and glutathione-S-transferase (GST). CDDP-induced renal dysfunction, structural damage and oxidative/nitrosative were prevented by tBHQ. In addition, tBHQ completely prevented the CDDP-induced fall in GPx and GST activities. In conclusion, the present study indicates that the antioxidant activity of tBHQ is associated with its nephroprotective effect against CDDP-induced acute kidney injury in rats.

Garlic Powder Ameliorates Cisplatin-Induced Nephrotoxicity and Oxidative Stress

cis-Diamminedichloroplatinum (II) (cisplatin) is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors. Nevertheless, nephrotoxicity has restricted its clinical use. The use of more than a few antioxidants has shown that reactive oxygen species are involved in cisplatin-induced nephrotoxicity. In the present work the effect of garlic powder, a recognized antioxidant, on cisplatin-induced nephrotoxicity and oxidative and nitrosative stress was studied. Rats were fed with a 2% garlic powder diet for 4 weeks. A single injection of cisplatin (7.5 mg/kg) induced tubular damage and an increase in the following markers of renal injury 3 days later: blood urea nitrogen, serum creatinine, and urinary excretion of N-acetyl-beta-D-glucosaminidase. The cisplatin injection also increased 3-nitrotyrosine and 4-hydroxy-2-nonenal immunostaining in renal cortex and medulla. It was found that the garlic powder feeding was able to prevent by 40-59% the alterations in the markers of renal injury studied, by 33% the histological damage, and by 38-75% the increase in markers of oxidative and nitrosative stress. It is concluded that the ability of garlic powder to ameliorate cisplatin-induced renal injury is associated with its antioxidant properties. Our data support the use of garlic powder as a renoprotective agent.

Serum angiotensin converting enzyme activity and plasma renin activity in experimental models of rats

1. Serum angiotensin converting enzyme activity (ACEA) and plasma renin activity (PRA) were determined in rats under different experimental conditions such as: nephrotic syndrome (NS), bilateral nephrectomy (BN), renovascular hypertension (RH), dehydration (DEH), anaesthesia (AN), low sodium diet (LSD) and high sodium diet (HSD), and injection with propranolol (PRO) and isoprenaline (ISO).

Effects of Ursodeoxycholic Acid on Hemodynamic and Renal Function Abnormalities Induced by Obstructive Jaundice in Rats

UNLABELLED The mechanism of renal function abnormalities in experimental biliary cirrhosis can be partially explained by the absence of gastrointestinal bile flow, which predisposes to translocation of intestinal endotoxin, a potent renal vasoconstrictor. Since bile acids prevent the absorption of intestinal endotoxins, we aimed to evaluate the effects of ursodeoxycholic acid (UDCA) administration on renal function and hemodynamic abnormalities induced by 1 week of obstructive jaundice in rats. METHODS Fifty-two rats were used; 30 had ligation of the common bile duct, 22 were sham operated. Bile duct ligated rats were randomly and blindly assigned to receive UDCA (25 mg/kg/day, n = 14) or placebo (n = 16) during 1 week. Sham rats received no treatment. Portal pressure (PP) as well as creatinine clearance (CrCl), urinary sodium (US), and plasma renin activity (PRA) were evaluated. Results are mean +/- SEM, with a significant value of p < 0.05. RESULTS Portal pressure (10.4 +/- 1.1 vs. 12.1 +/- 0.8 mm Hg) was significantly lower in UDCA than in placebo-treated rats. ALT serum levels were also significantly lower in bile duct ligated rats receiving UDCA (77.3 +/- 28 IU/L) than in placebo-treated rats (162 +/- 65 IU/L). US (1.1 +/- 0.5 vs. 2.1 +/- 0.3 mEq/24 h) was significantly lower and PRA (6.0 +/- 2.6 vs. 1.9 +/- 1.0 ng Ang 1/mL/h) higher in bile duct ligated than in sham-operated rats. No differences were found between UDCA or placebo-treated bile duct ligated rats. CrCl was similar between sham (0.39 +/- 0.12 mL/min/100 g BW) and UDCA (0.32 +/- 0.16) but significantly lower in placebo-treated (0.28 +/- 0.07) than sham-operated rats (p < 0.05). CONCLUSION UDCA administration had very mild effects on renal function abnormalities induced by experimental obstructive jaundice in rats. However, portal hypertension and biochemical abnormalities were partially improved.

Copper and Zinc Metabolism in Aminonucleoside-Induced Nephrotic Syndrome

Copper (Cu) and zinc (Zn) were measured in urine, serum and tissues from rats with nephrotic syndrome (NS) induced with a single subcutaneous dose of puromycin aminonucleoside (PAN; 15 mg/100 g BW). Control animals were pair-fed. Urine was collected daily, and the rats were sacrificed on day 10. PAN-nephrotic rats had proteinuria (days 3-10), high urinary Cu (days 1, 2, 4-10) and Zn (days 3-10) excretion. On day 10, nephrotic rats had: (a) albuminuria, hypoalbuminemia, hypoproteinemia, high urine and low serum levels of ceruloplasmin; (b) low Cu and Zn serum levels; (c) high clearance and fractional excretion of Cu and Zn, and (d) low kidney and liver Cu content and essentially normal tissue Zn levels. The alterations in Cu metabolism were more intense than those in Zn metabolism. Urine Cu and Zn showed a positive correlation with urine total protein on days 3-10 which suggests that high urinary excretion of Cu and Zn may be due to the excretion of its carrier proteins. In conclusion, these rats did not show a typical Zn deficiency but a clear decrease in Cu in the liver and kidney.