Biomedical subjects

Mike E C Robbins

Publications and source records attributed to Mike E C Robbins.

3 recordsLinked to original sources

PubMed2004

Radiation-induced up-regulation of Mmp2 involves increased mRNA stability, redox modulation, and MAPK activation.

We have previously observed time- and dose-dependent increases in matrix metalloproteinase 2 (Mmp2) protein levels in rat tubule epithelial cells (NRK52E) after irradiation. However, the mechanism(s) involved remains unclear. In the present study, irradiating NRK52E cells with 0-20 Gy gamma rays was associated with time- and dose-dependent increases in Mmp2 mRNA. Studies using the transcription inhibitor actinomycin D (ActD) added 24 h after irradiation revealed the t(1/2) of Mmp2 mRNA to be approximately 8 h in control cells. In contrast, the increase in Mmp2 mRNA levels in irradiated cells was essentially unchanged after incubation with ActD for up to 12 h. Incubating cells with the antioxidants N-acetylcysteine or ebselen or the MEK pathway inhibitors PD98059 and U0126 prior to irradiation abolished the radiation-induced up-regulation of Mmp2. Irradiating NRK52E cells led to reactive oxygen species-mediated Erk1/2 activation; preincubation with NAC prevented the radiation-induced increase in phosphorylated Erk1/2. Transfecting cells with a dominant-negative ERK mutant completely inhibited radiation-induced Erk phosphorylation and abolished the radiation-induced up-regulation of Mmp2 protein. Thus the radiation-induced up-regulation of Mmp2 mRNA is due in part to increased mRNA stability and is mediated by redox; the ERK MAPK signaling pathway may be involved.

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PubMed2003

Radiation nephropathy.

The pronounced radiosensitivity of renal tissue limits the total radiotherapeutic dose that can be applied safely to treatment volumes that include the kidneys. The incidence of clinical radiation nephropathy has increased with the use of total-body irradiation (TBI) in preparation for bone marrow transplantation and as a consequence of radionuclide therapies. The clinical presentation is azotemia, hypertension, and, disproportionately, severe anemia seen several months to years after irradiation that, if untreated, leads to renal failure. Structural features include mesangiolysis, sclerosis, tubular atrophy, and tubulointerstitial scarring. Similar changes are seen in a variety of experimental animal models. The classic view of radiation nephropathy being inevitable, progressive, and untreatable because of DNA damage-mediated cell loss at division has been replaced by a new paradigm in which radiation-induced injury involves not only direct cell kill but also involves complex and dynamic interactions between glomerular, tubular, and interstitial cells. These serve both as autocrine and as paracrine, if not endocrine, targets of biologic mediators that mediate nephron injury and repair. The renin angiotensin system (RAS) clearly is involved; multiple experimental studies have shown that antagonism of the RAS is beneficial, even when not initiated until weeks after irradiation. Recent findings suggest a similar benefit in clinical radiation nephropathy.

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PubMed2002

Identification of a functional peroxisome proliferator-activated receptor response element in the rat catalase promoter.

Peroxisomal proliferator-activated receptor (PPAR)gamma has been shown to decrease the inflammatory response via transrepression of proinflammatory transcription factors. However, the identity of PPARgamma responsive genes that decrease the inflammatory response has remained elusive. Because generation of the reactive oxygen species hydrogen peroxide (H(2)O(2)) plays a role in the inflammatory process and activation of proinflammatory transcription factors, we wanted to determine whether the antioxidant enzyme catalase might be a PPARgamma target gene. We identified a putative PPAR response element (PPRE) containing the canonical direct repeat 1 motif, AGGTGA-A-AGTTGA, in the rat catalase promoter. In vitro translated PPARgamma and retinoic X receptor-alpha proteins were able to bind to the catalase PPRE. Promoter deletion analysis revealed that the PPRE was functional, and a heterologous promoter construct containing a multimerized catalase PPRE demonstrated that the PPRE was necessary and sufficient for PPARgamma-mediated activation. Treatment of microvascular endothelial cells with PPARgamma ligands led to increases in catalase mRNA and activity. These results demonstrate that PPARgamma can alter catalase expression; this occurs via a PPRE in the rat catalase promoter. Thus, in addition to transrepression of proinflammatory transcription factors, PPARgamma may also be modulating catalase expression, and hence down-regulating the inflammatory response via scavenging of reactive oxygen species.

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