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

Abstract

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-κB) 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-κB 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 mm 2 . 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-κB 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-κB. The increased expression of p-p38 MAPK and NF-κB observed in these rats suggests that these signaling molecules may be involved in the pathogenesis of tubulointerstitial nephritis induced by gentamicin.

Candesartan and epigallocatechin‐3‐gallate ameliorate gentamicin‐induced renal damage in rats through p38‐MAPK and NF‐κB pathways

“…This result is in accordance with our study. It is assumed that p38‐MAPK modulates the activation of NF‐κB p65 and plays a critical role in producing proinflammatory cytokines, including IL‐1β and TNF‐α as well as controlling cell apoptosis in renal injury . The present experiment revealed a notable upregulation of p38‐MAPK and caspase‐3 levels in gentamicin‐treated rats.…”

Protective Effects ofN-Acetylcysteine Amide (NACA) on Gentamicin-Induced Apoptosis in LLC-PK1 Cells

“…This confirms a previous report that p38 MAPK is involved in Geninduced apoptosis. 15 Since iNOS induction by Gen was inhibited by the p38-MAPK inhibitor SB203580, we suggest that p38 MAPK acts upstream of iNOS in the cascade of Gen-induced apoptosis. Induction of iNOS by p38 MAPK has been demonstrated previously, [16][17][18] and iNOS-derived NO is a key molecule in tubular epithelial apoptosis induced by different toxic agents.…”

Treatment with a p38 MAPK inhibitor attenuates cisplatin nephrotoxicity starting after the beginning of renal damage

“…Recent studies have provided evidence supporting the involvement of p38 MAPK in acute renal failure (ARF) induced by renal toxicants, including gentamicin (Volpini et al 2006) and CP (Ramesh and Reeves 2005). The role of reactive oxygen species (ROS) in mediating CP-induced renal injury was also demonstrated as the results from Tsuruya et al (2003) suggest that antioxidants can ameliorate CP-induced acute renal failure through inactivation of the death receptor-mediated apoptotic pathways.…”

“…The membranebound antibody was detected using the Supersignal West Pico Chemiluminescent substrate (Pierce, Rockford, IL, USA) and captured on X-ray film. The intensity of the identified lanes was quantified by densitometry using ImageJ NIH image software and was reported in arbitrary units (Volpini et al 2006).…”