Previous exposure to cigarette smoke aggravates experimental cyclosporine-induced nephrotoxicity.

BACKGROUND/AIMS: The effects of cigarette smoke (CS) on cyclosporine (CsA)-induced nephrotoxicity are poorly studied. This study aims to assess the effects of previous exposure to CS on CsA nephrotoxicity. METHODS: Rats were either exposed to CS or sham (S) procedures for 10 min twice a day for 20 weeks. From the 16th to the 20th week, they received a low-salt diet. Beginning with the 17th week, they were given 2.5 mg/day CsA or vehicle (VH) for 3 weeks. The final groups were VH/CS, CsA/CS, VH/S, and CsA/S. On day 141, glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), tubulointerstitial fibrosis, and CsA blood levels were measured and immunohistochemistry was analyzed for renal α-smooth muscle actin (SMA), nitrotyrosine, and vimentin. RESULTS: CsA decrease in GFR was enhanced by CS exposure. CsA associated with CS induced higher periglomerular α-SMA and renal nitrotyrosine expression. CsA decreased RBF, but increased RVR, tubulointerstitial fibrosis, and α-SMA and renal vimentin expression. These changes and the CsA blood levels were not affected by CS exposure. CONCLUSION: CS aggravated the CsA-induced impairment of GFR and CS associated with CsA caused the development of periglomerular structural lesions and oxidative stress in a rat model of CsA nephrotoxicity.

Loxosceles gaucho venom-induced acute kidney injury--in vivo and in vitro studies.

BACKGROUND: Accidents caused by Loxosceles spider may cause severe systemic reactions, including acute kidney injury (AKI). There are few experimental studies assessing Loxosceles venom effects on kidney function in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In order to test Loxosceles gaucho venom (LV) nephrotoxicity and to assess some of the possible mechanisms of renal injury, rats were studied up to 60 minutes after LV 0.24 mg/kg or saline IV injection (control). LV caused a sharp and significant drop in glomerular filtration rate, renal blood flow and urinary output and increased renal vascular resistance, without changing blood pressure. Venom infusion increased significantly serum creatine kinase and aspartate aminotransferase. In the LV group renal histology analysis found acute epithelial tubular cells degenerative changes, presence of cell debris and detached epithelial cells in tubular lumen without glomerular or vascular changes. Immunohistochemistry disclosed renal deposition of myoglobin and hemoglobin. LV did not cause injury to a suspension of fresh proximal tubules isolated from rats. CONCLUSIONS/SIGNIFICANCE: Loxosceles gaucho venom injection caused early AKI, which occurred without blood pressure variation. Changes in glomerular function occurred likely due to renal vasoconstriction and rhabdomyolysis. Direct nephrotoxicity could not be demonstrated in vitro. The development of a consistent model of Loxosceles venom-induced AKI and a better understanding of the mechanisms involved in the renal injury may allow more efficient ways to prevent or attenuate the systemic injury after Loxosceles bite.

Loxosceles gaucho Venom-Induced Acute Kidney Injury In Vivo and In Vitro Studies

Accidents caused by Loxosceles spider may cause severe systemic reactions, including acute kidney injury(AKI). There are few experimental studies assessing Loxosceles venom effects on kidney function in vivo.In order to test Loxosceles gaucho venom (LV) nephrotoxicity and to assess some of the possible mechanisms of renal injury, rats were studied up to 60 minutes after LV 0.24 mg/kg or saline IV injection (control). LV caused a sharp and significant drop in glomerular filtration rate, renal blood flow and urinary output and increased renal vascular resistance, without changing blood pressure. Venom infusion increased significantly serum creatine kinase and aspartate aminotransferase. In the LV group renal histology analysis found acute epithelial tubular cells degenerative changes, presence of cell debris and detached epithelial cells in tubular lumen without glomerular or vascular changes.Immunohistochemistry disclosed renal deposition of myoglobin and hemoglobin. LV did not cause injury to a suspension of fresh proximal tubules isolated from rats.

The effects of so-called 'forbidden acupuncture points' on pregnancy outcome in wistar rats.

BACKGROUND: This study sought to determine if acupuncture in LI4 and SP6, or in sacral points could harm the pregnancy outcome in Wistar rats as is believed according to traditional knowledge. METHODS: 48 pregnant Wistar rats were randomly divided into 4 groups: total control where the rats were left in cages without manipulation; anesthetized control where the rats were manipulated and anesthetized but did not received electroacupuncture; peripheral points and sacral points were the rats were anesthetized and received 4 acupuncture points - LI4-SP6 and BL27-28, respectively. The primary end point was embryonic loss after implantation, defined as (number of implantations - number of embryos in development) × 100 / number of implantations. Other evaluated parameters were fetal death, abortions, number of fetuses, and resorptions, resorption index (number of resorptions / total of implantations), maternal weight gain, and fetal weight. RESULTS: There were no differences in embryonic loss after implantation (p = 0.45), fetal death (p = 1), abortions (p = 1), number of fetuses (p = 0.79), resorptions (p = 0.3), and resorption index (p = 0.45). There were differences in maternal weight gain and fetal weight, but they seemed unrelated to the treatment. CONCLUSIONS: We found no evidence that acupuncture in LI4-SP6 and sacral points could be harmful to the pregnancy outcome in Wistar rats.

Annexin 1 mimetic peptide protects against renal ischemia/reperfusion injury in rats.

Inflammation is currently recognized as a key mechanism in the pathogenesis of renal ischemia-reperfusion (I/R) injury. The importance of infiltrating neutrophil, lymphocytes, and macrophage in this kind of injury has been assessed with conflicting results. Annexin 1 is a protein with potent neutrophil anti-migratory activity. In order to evaluate the effects of annexin A1 on renal I/R injury, uninephrectomized rats received annexin A1 mimetic peptide Ac2-26 (100 µg) or vehicle before 30 min of renal artery clamping and were compared to sham surgery animals. Annexin A1 mimetic peptide granted a remarkable protection against I/R injury, preventing glomerular filtration rate and urinary osmolality decreases and acute tubular necrosis development. Annexin A1 infusion aborted neutrophil extravasation and attenuated macrophage infiltration but did not prevent tissue lymphocyte traffic. I/R increased annexin A1 expression (assessed by transmission electron microscopy) in renal epithelial cells, which was attenuated by exogenous annexin A1 infusion. Additionally, annexin A1 reduced I/R injury in isolated proximal tubules suspension. Annexin A1 protein afforded striking functional and structural protection against renal I/R. These results point to an important role of annexin A1 in the epithelial cells defense against I/R injury and indicate that neutrophils are key mediators for the development of tissue injury after renal I/R. If these results were confirmed in clinical studies, annexin A1 might emerge as an important tool to protect against I/R injury in renal transplantation and in vascular surgery.

Macrophage depletion attenuates chronic cyclosporine A nephrotoxicity.

BACKGROUND: Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized by renal dysfunction and interstitial fibrosis. Early and progressive renal macrophage influx, correlating with latter interstitial fibrotic areas, has been associated with CsA treatment. This study investigated the role of macrophages, the nitric oxide (NO) pathway, and the oxidative stress on chronic CsA nephrotoxicity. METHODS: The macrophages were depleted by clodronate liposomes. Animals were distributed into four groups: vehicle (olive oil for 21 days), CsA 7.5 mg/kg per day (21 days), CsA plus clodronate (5 mg/mL intraperitoneally on days -4, 1, 4, 11, and 18 of CsA treatment), or vehicle plus clodronate. On day 22, glomerular filtration rate, renal blood flow, renal tubulointerstitial fibrosis, CsA blood levels, serum malondialdehyde and renal tissue immunohistochemistry for macrophages, inducible NO synthase, transforming growth factor-beta, nuclear factor-kbeta, alpha-smooth muscle actin, vimentin, and nitrotyrosine were assessed. RESULTS: CsA-induced increase in the macrophage was prevented by clodronate. Macrophage depletion attenuated the reductions in the glomerular filtration rate and renal blood flow, the development of tubulointerstitial fibrosis, malondialdehyde increase and increases in nuclear factor-kbeta, transforming growth factor-beta, vimentin, inducible NO synthase, and nitrotyrosine expression provoked by CsA. Clodronate did not affect alpha-smooth muscle actin expression and CsA blood levels. CONCLUSIONS: Renal macrophage influx plays an important role in CsA-induced chronic nephrotoxicity. The NO pathway and oxidative stress are likely mechanisms involved in the genesis of this form of renal injury.

Interaction of the anti-inflammatory annexin A1 protein and tacrolimus immunosuppressant in the renal function of rats.

BACKGROUND: Tacrolimus (FK) is currently widely used in transplant immunosuppression and the treatment of autoimmune diseases. However, FK induces nephrotoxicity which is characterized by functional and structural renal injury. The ubiquitous protein annexin A1 (ANXA1) has potent anti-inflammatory effects and protects against ischemia/reperfusion injury. We investigated the effects of exogenous ANXA1 treatment in an experimental model of acute FK nephrotoxicity. METHODS: Munich-Wistar rats received a low-salt diet for 1 week and were randomized to treatment with ANXA1 (Ac2-26 peptide 0.5 mg/kg/day s.c.), FK (6 mg/kg/day p.o.), association (FK+ANXA1) and vehicles (1 ml/kg/day) for 7 days. RESULTS: FK induced a significant decrease in glomerular filtration rate and renal blood flow, and a significant increase in renal vascular resistance. In addition, FK caused extensive acute tubule-interstitial damage and an increase in anti-inflammatory ANXA1 expression in renal tissue. Exogenous ANXA1 treatment reduced FK-induced tubular dilatation and macrophage infiltration. For the first time, we observed that FK augmented ANXA1 expression in renal tissue. CONCLUSION: Exogenous ANXA1 treatment partially protected against FK-induced tubular injury and macrophage infiltration, and may be targeted in renal intervention strategies.

Ga-67 scintigraphy in the differential diagnosis between acute interstitial nephritis and acute tubular necrosis: an experimental study.

BACKGROUND: The differentiation between acute interstitial nephritis (AIN) and acute tubular necrosis (ATN) is crucial in patients with acute kidney injury. Gallium-67 citrate (Ga-67) has been used clinically in the differential diagnosis between these entities, but its efficacy is disputed. The aim of this study was to evaluate Ga-67 scintigraphy efficacy in the differentiation between experimental models of drug-induced AIN and ATN. METHODS: Animals were divided into three groups: AIN (n = 8), ATN (n = 8) and control (NL, n = 10). The AIN group received intraperitoneal puromycin aminonucleoside (single dose, 150 mg/kg). The ATN group received a single intraperitoneal injection of cisplatin (6 mg/kg). The NL group did not receive active drugs. All of the animals were submitted to Ga-67 scintigraphy, serum creatinine (Cr) and urinary osmolality assessment, and blinded renal histology evaluation. RESULTS: Renal Ga-67 uptake was strikingly more intense in the AIN group when compared to the ATN (P < 0.0001) and NL (P < 0.001) groups. The ATN group had increased Cr when compared to the NL group (P < 0.001) and lower urinary osmolality vs the NL (P < 0.001) and AIN (P < 0.01) groups. Renal histology showed severe acute tubular injury in the ATN group and intense interstitial inflammation in the AIN group, and was normal in control animals. CONCLUSION: Ga-67 scintigraphy was extremely effective in the differentiation between experimental drug-induced ATN and AIN.

In vivo effects of Bothrops jararaca venom on metabolic profile and on muscle protein metabolism in rats.

This study investigated the in vivo effects of the Bothrops jararaca venom (BjV) on general metabolic profile and, specifically, on muscle protein metabolism in rats. The crude venom (0.4 mg/kg body weight, IV) was infused in awake rats, and plasma activity of enzymes and metabolites levels were determined after 1, 2, 3, and 4 hours. BjV increased urea, lactate, and activities of creatine kinase, lactate dehydrogenase, and aspartate aminotransferase after 4 hours. The content of liver glycogen was reduced by BjV. Protein metabolism was evaluated by means of microdialysis technique and in isolated muscles. BjV induced increase in the muscle interstitial-arterial tyrosine concentration difference, indicating a high protein catabolism. The myotoxicity induced by this venom is associated with reduction of protein synthesis and increase in rates of overall proteolysis, which was accompanied by activation of lysosomal and ubiquitin-proteasome systems without changes in protein levels of cathepsins and ubiquitin-protein conjugates.

Mechanisms of bee venom-induced acute renal failure.

The spread of Africanized bees in the American continent has increased the number of severe envenomation after swarm attacks. Acute renal failure (ARF) is one of the major hazards in surviving patients. To assess the mechanisms of bee venom-induced ARF, rats were evaluated before, up to 70 min and 24h after 0.5mg/kg of venom injection. Control rats received saline. Bee venom caused an early and significant reduction in glomerular filtration rate (GFR, inulin clearance, 0.84+/-0.05 to 0.40+/-0.08 ml/min/100g, p<0.0001) and renal blood flow (RBF, laser Doppler flowmetry), which was more severe in the cortical (-72%) than in the medullary area (-48%), without systemic blood pressure decrease. Creatine phosphokinase, lactic dehydrogenase (LDH) and serum glutamic oxaloacetic transaminase increased significantly, pointing to rhabdomyolysis, whereas serum glutamic pyruvic transaminase and hematocrit remained stable. Twenty-four hours after venom, RBF recovered but GFR remained significantly impaired. Renal histology showed acute tubular injury and a massive tubular deposition of myoglobin. Venom was added to isolated rat proximal tubules (PT) suspension subjected to normoxia and hypoxia/reoxygenation (H/R) for direct nephrotoxicity evaluation. After 60 min of incubation, 0.1, 2 and 10 microg of venom induced significant increases in LDH release: 47%, 64% and 86%, respectively, vs. 21% in control PT while 2 microg of venom enhanced H/R injury (85% vs. 55%, p<0.01). These results indicate that vasoconstriction, direct nephrotoxicity and rhabdomyolysis are important mechanisms in the installation of bee venom-induced ARF that may occur even without hemolysis or hypotension.

Acute intoxication due to ingestion of vegetables contaminated with aldicarb.

Three members of the same family ingested vegetables treated with aldicarb. All three developed signs and symptoms of acetylcholinesterase inhibition and all recovered a few hours after the ingestion. Reports of toxicity from the ingestion of aldicarb-contaminated food are uncommon. Aldicarb is a potent pesticide which can only be used safely if governmental and industry regulations are followed carefully.