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      Inhibition of Nuclear Factor-κB Activation Attenuates Tubulointerstitial Nephritis Induced by Gentamicin

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          Background: Animals treated with gentamicin can show residual areas of interstitial fibrosis in the renal cortex. This study investigated the expression of nuclear factor-ĸB (NF-ĸB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate (PDTC), an NF-ĸB inhibitor. Methods: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + PDTC, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. Results: Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-ĸB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented fibrosis in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by gentamicin. Conclusions: These data show that inhibition of NF-ĸB activation attenuates tubulointerstitial nephritis induced by gentamicin.

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          Most cited references 13

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              Transcription factor-kappa B (NF-kappa B) and renal disease.

               C Guijarro,  J. Egido (2001)
              Transcription factor-kappa B (NF-kappa B) and renal disease. Nuclear factor-kappa B (NF-kappa B) comprises a family of dimeric transcription factors that regulate the expression of numerous genes involved in inflammation and cell proliferation. Although NF-kappa B was initially identified in lymphocytes, it has been found to be a transcription factor present in virtually all cell types. In resting cells, NF-kappa B dimers remain in the cytoplasm in an inactive form bound to the inhibitory subunit I kappa B. Upon stimulation, I kappa B is phosphorylated, ubiquitinylated, and ultimately degraded by proteolytic cleavage by the proteasome system. As a result, NF-kappa B dimers are translocated into the nucleus and activate the transcription of target genes. Increasing data suggest a pivotal role for NF-kappa B in a variety of pathophysiological conditions in which either inflammation or cell number control are critical events. NF-kappa B has been found to be activated in experimental renal disease. Importantly, both in vivo and in vitro, NF-kappa B activation can be modulated by pharmacological maneuvers. Indeed, it is now widely acknowledged that the anti-inflammatory action of steroids is basically obtained through the inhibition of the transactivation of NF-kappa B-dependent genes. In addition, some of the beneficial effects of angiotensin-converting enzyme inhibitors and statins may, at least in part, be mediated by an inhibition of NF-kappa B activation. A better understanding of the mechanisms involved in NF-kappa B regulation and its modulation may provide new tools to improve the treatment of renal diseases with a better sound pathophysiological approach.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                December 2004
                20 December 2004
                : 98
                : 4
                : p97-p106
                Departments of aPhysiology and bPathology, Faculty of Medicine, Ribeirão Preto, Brazil
                81558 Nephron Physiol 2004;98:p97–p106
                © 2004 S. Karger AG, Basel

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                Figures: 6, Tables: 2, References: 29, Pages: 1
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