Renoprotective effect of N-acetylcysteine depends upon the severity of the ischemia reperfusion injury.

Acute kidney injury (AKI) is a common complication in seriously ill patients, while renal ischemia-reperfusion (I/R) injury is the most frequent event in this oxidative renal injury. N-acetylcysteine (NAC) is a small molecule containing a thiol group that has antioxidant properties, promoting detoxification and acting directly as a free radical scavenger. In this study, the protective effect of NAC was investigated in short-term (30 min) and long-term (45 min) ischemic AKI. This was achieved via clamping of the renal artery for 30 or 45 min in Wistar rats to induce I/R injury. AKI worsened with a longer period of ischemia (45 compared to 30 min) due to probable irreversible damage. Preconditioning with NAC in short-term ischemia improved renal blood flow and increased creatinine clearance by reducing oxidative metabolites and increasing antioxidant capacity. Otherwise, NAC did not change these parameters in the long-term ischemia. Therefore, this study demonstrated that the period of ischemia determines the severity of the AKI, and NAC presented antioxidant effects in short-term ischemia but not in long-term ischemia, confirming that there is a possible therapeutic window for its renoprotective effect.

Renoprotective effect of N-acetylcysteine depends upon the severity of the ischemia reperfusion injury

Acute kidney injury (AKI) is a common complication in seriously ill patients, while renal ischemia-reperfusion (I/R) injury is the most frequent event in this oxidative renal injury. N-acetylcysteine (NAC) is a small molecule containing a thiol group that has antioxidant properties, promoting detoxification and acting directly as a free radical scavenger. In this study, the protective effect of NAC was investigated in short-term (30 min) and long-term (45 min) ischemic AKI. This was achieved via clamping of the renal artery for 30 or 45 min in Wistar rats to induce I/R injury. AKI worsened with a longer period of ischemia (45 compared to 30 min) due to probable irreversible damage. Preconditioning with NAC in short-term ischemia improved renal blood flow and increased creatinine clearance by reducing oxidative metabolites and increasing antioxidant capacity. Otherwise, NAC did not change these parameters in the long-term ischemia. Therefore, this study demonstrated that the period of ischemia determines the severity of the AKI, and NAC presented antioxidant effects in short-term ischemia but not in long-term ischemia, confirming that there is a possible therapeutic window for its renoprotective effect.

Up-regulation of renal renin-angiotensin system and inflammatory mechanisms in the prenatal programming by low-protein diet: beneficial effect of the post-weaning losartan treatment.

Previous studies have shown that the renin-angiotensin system (RAS) is affected by adverse maternal nutrition during pregnancy. The aim of this study was to investigate the effects of a maternal low-protein diet on proinflammatory cytokines, reactive oxygen species and RAS components in kidney samples isolated from adult male offspring. We hypothesized that post-weaning losartan treatment would have beneficial effects on RAS activity and inflammatory and oxidative stress markers in these animals. Pregnant Sprague-Dawley rats were fed with a control (20% casein) or low-protein diet (LP) (6% casein) throughout gestation. After weaning, the LP pups were randomly assigned to LP and LP-losartan groups (AT1 receptor blockade: 10 mg/kg/day until 20 weeks of age). At 20 weeks of age, blood pressure levels were higher and renal RAS was activated in the LP group. We also observed several adverse effects in the kidneys of the LP group, including a higher number of CD3, CD68 and proliferating cell nuclear antigen-positive cells and higher levels of collagen and reactive oxygen species in the kidney. Further, our results revealed that post-weaning losartan treatment completely abolished immune cell infiltration and intrarenal RAS activation in the kidneys of LP rats. The prevention of augmentation of angiotensin (Ang II) concentration abolished inflammatory and fibrotic events, indicating that Ang II via the AT1 receptor is essential for pathological initiation. Our results suggest that the prenatal programming of hypertension is dependent on the up-regulation of local RAS and presence of immune cells in the kidney.

Increased expression of p38 mitogen-activated protein kinase is related to the acute renal lesions induced by gentamicin.

Mitogen-activated protein kinases (MAPK) may be involved in the pathogenesis of acute renal failure. This study investigated the expression of p-p38 MAPK and nuclear factor kappa B (NF-kappaB) in the renal cortex of rats treated with gentamicin. Twenty rats were injected with gentamicin, 40 mg/kg, i.m., twice a day for 9 days, 20 with gentamicin + pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor), 14 with 0.15 M NaCl, i.m., twice a day for 9 days, and 14 with 0.15 M NaCl , i.m., twice a day for 9 days and PDTC, 50 mg kg(-1) day(-1), i.p., twice a day for 15 days. The animals were killed 5 and 30 days after the last of the injections and the kidneys were removed for histological, immunohistochemical and Western blot analysis and for nitrate determination. The results of the immunohistochemical study were evaluated by counting the p-p38 MAPK-positive cells per area of renal cortex measuring 0.05 mm2. Creatinine was measured by the Jaffé method in blood samples collected 5 and 30 days after the end of the treatments. Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. In addition, animals killed 5 days after the end of gentamicin treatment presented acute tubular necrosis and increased nitrate levels in the renal cortex. Increased expression of p-p38 MAPK and NF-kappaB was also observed in the kidneys from these animals. The animals killed 30 days after gentamicin treatment showed residual areas of interstitial fibrosis in the renal cortex, although the expression of p-p38 MAPK in their kidneys did not differ from control. Treatment with PDTC reduced the functional and structural changes induced by gentamicin as well as the expression of p-p38 MAPK and NF-kappaB. The increased expression of p-p38 MAPK and NF-kappaB observed in these rats suggests that these signaling molecules may be involved in the pathogenesis of tubulointerstitial nephritis induced by gentamicin.

Increased expression of p38 mitogen- activated protein kinase is related to the acute renal lesions induced by gentamicin

Mitogen-activated protein kinases (MAPK) may be involved in the pathogenesis of acute renal failure. This study investigated the expression of p-p38 MAPK and nuclear factor kappa B (NF-kappaB) in the renal cortex of rats treated with gentamicin. Twenty rats were injected with gentamicin, 40 mg/kg, im, twice a day for 9 days, 20 with gentamicin + pyrrolidine dithiocarbamate (PDTC, an NF-kappaB inhibitor), 14 with 0.15 M NaCl, im, twice a day for 9 days, and 14 with 0.15 M NaCl , im, twice a day for 9 days and PDTC, 50 mg kg-1 day-1, ip, twice a day for 15 days. The animals were killed 5 and 30 days after the last of the injections and the kidneys were removed for histological, immunohistochemical and Western blot analysis and for nitrate determination. The results of the immunohistochemical study were evaluated by counting the p-p38 MAPK-positive cells per area of renal cortex measuring 0.05 mm². Creatinine was measured by the Jaffé method in blood samples collected 5 and 30 days after the end of the treatments. Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. In addition, animals killed 5 days after the end of gentamicin treatment presented acute tubular necrosis and increased nitrate levels in the renal cortex. Increased expression of p-p38 MAPK and NF-kappaB was also observed in the kidneys from these animals. The animals killed 30 days after gentamicin treatment showed residual areas of interstitial fibrosis in the renal cortex, although the expression of p-p38 MAPK in their kidneys did not differ from control. Treatment with PDTC reduced the functional and structural changes induced by gentamicin as well as the expression of p-p38 MAPK and NF-kappaB. The increased expression of p-p38 MAPK and NF-kappaB observed in these rats suggests that these signaling molecules may be involved in the pathogenesis of tubulointerstitial nephritis induced by gentamicin.

Tubular cell lesion, albuminuria, and renal albumin handling in rats treated with adriamycin.

Several lines of evidence have suggested that renal handling of proteins in rats with several nephropathies may contribute to the tubulointerstitial damage observed in these animals. It has been suggested that proteins filtered by the glomeruli may be toxic for tubule cells. The aim of this study was to investigate the relationship between albuminuria and tubular lesions observed in rats during the first two weeks after treatment with adriamycin (AD). Thirty female Wistar rats were injected intravenously with adriamycin at the dose of 3.5 (17 rats) or 5mg/kg body weight (13 rats), and 7 were injected with 0.15 M NaCl (control group). Seven days later, we replaced drinking water with a 0.10 M sodium bicarbonate solution for 6 of the animals injected with 5 mg/kg adriamycin (group AD-B). Urine samples were collected before and 7 and 15 days after treatment to quantify albumin. The rats were killed 7 and 18 days after the injections, and the kidneys removed for immunohistochemical study. We observed a significant increase in urinary albumin excretion 15 days after AD injection (3.5 mg/kg), but not 7 days after AD. However, in the animals injected with 5.0 mg/kg AD (group AD-5) the increase in albuminuria was observed as early as on day 7. The immunohistochemical studies showed increased vimentin and albumin immunoreaction in the tubular cells of the renal cortex from the kidneys of rats injected with 3.5 mg/kg (group AD-3) only 18 days after treatment (p < 0.05), whereas in the animals treated with 5 mg/kg AD these immunohistochemical alterations were more intense. However, treatment with sodium bicarbonate attenuated the tubular lesions and reduced albumin reabsorption in adriamycin-treated rats. In conclusion, these experiments showed a relationship between albuminuria and tubular lesions in adriamycin-treated rats.