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      Attenuation of Glycerol-Induced Acute Kidney Injury by Previous Partial Hepatectomy: Role of Hepatocyte Growth Factor/c-met Axis in Tubular Protection

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          Background/Aims: Previous partial hepatectomy (HPTX) can attenuate glycerol-induced acute kidney injury (Gly-AKI). The aim of this study was to explore the pathophysiological mechanisms and the role of hepatocyte growth factor (HGF) in kidney protection. Methods: Rats were subjected to HPTX 24 h before glycerol administration. Renal function, acute tubular necrosis, apoptosis, leukocyte infiltration, and the expression of HGF, c-met, monocyte chemoattractant protein-1, interleukin-1β, and heme oxygenase-1 were evaluated 24 h after glycerol injection. The regenerative response was analyzed from 6 to 72 h after glycerol injection (BrdU incorporation). In a separate series of experiments, Gly-AKI+HPTX rats were treated with anti-HGF antibody. Results: Gly-AKI+HPTX rats showed an increased expression of renal HGF and c-met as well as an improved creatinine clearance and reduced acute tubular necrosis and apoptosis, cytokine expression, and leukocyte infiltration. The regenerative response was less intense 24 and 72 h after glycerol administration in this group. The anti-HGF treatment disclosed an important role of HGF in the reduction of tubular injury, particularly apoptosis. Overexpression of heme oxygenase-1 was observed in Gly-AKI+HPTX rats, but was not associated with HPTX-induced renal protection. Conclusion: We conclude that Gly-AKI+HPTX rats have a reduced susceptibility to renal injury instead of an increased regenerative response and that endogenous HGF overexpression is responsible for suppression of tubular apoptosis.

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          Most cited references 29

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          Molecular cloning and expression of human hepatocyte growth factor.

          Hepatocyte growth factor (HGF) is the most potent mitogen for mature parenchymal hepatocytes in primary culture, and seems to be a hepatotrophic factor that acts as a trigger for liver regeneration after partial hepatectomy and liver injury. The partial purification and characterization of HGF have been reported. We have demonstrated that pure HGF from rat platelets is a new growth factor effective at concentrations as low as 1 ng ml-1. The effects of HGF and epidermal growth factor (EGF) are additive. The activity of HGF is not species-specific, although it does not stimulate growth in Swiss 3T3 fibroblasts. HGF has a relative molecular mass (Mr) of 82,000 and is a heterodimer composed of a large alpha-subunit of Mr 69,000 and a small beta-subunit of Mr 34,000. Here we report the amino-acid sequence of human HGF determined by complementary DNA cloning and the expression of biologically active human HGF from COS-1 cells transfected with cloned cDNA. The nucleotide sequence of the human HGF cDNA reveals that both alpha- and beta-chains are contained in a single open reading frame coding for a pre-pro precursor protein of 728 amino acids.
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            Ischemic acute renal failure: an inflammatory disease?

            Inflammation plays a major role in the pathophysiology of acute renal failure resulting from ischemia. In this review, we discuss the contribution of endothelial and epithelial cells and leukocytes to this inflammatory response. The roles of cytokines/chemokines in the injury and recovery phase are reviewed. The ability of the mouse kidney to be protected by prior exposure to ischemia or urinary tract obstruction is discussed as a potential model to emulate as we search for pharmacologic agents that will serve to protect the kidney against injury. Understanding the inflammatory response prevalent in ischemic kidney injury will facilitate identification of molecular targets for therapeutic intervention.
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              To be, or not to be: NF-kappaB is the answer--role of Rel/NF-kappaB in the regulation of apoptosis.

              During their lifetime, cells encounter many life or death situations that challenge their very own existence. Their survival depends on the interplay within a complex yet precisely orchestrated network of proteins. The Rel/NF-kappaB signaling pathway and the transcription factors that it activates have emerged as critical regulators of the apoptotic response. These proteins are best known for the key roles that they play in normal immune and inflammatory responses, but they are also implicated in the control of cell proliferation, differentiation, apoptosis and oncogenesis. In recent years, there has been remarkable progress in understanding the pathways that activate the Rel/NF-kappaB factors and their role in the cell's decision to either fight or surrender to apoptotic challenge. Whereas NF-kappaB is most commonly involved in suppressing apoptosis by transactivating the expression of antiapoptotic genes, it can promote programmed cell death in response to certain death-inducing signals and in certain cell types. This review surveys our current understanding of the role of NF-kappaB in the apoptotic response and focuses on many developments since this topic was last reviewed in Oncogene 4 years ago. These recent findings shed new light on the activity of NF-kappaB as a critical regulator of apoptosis in the immune, hepatic, epidermal and nervous systems, on the mechanisms through which it operates and on its role in tissue development, homoeostasis and cancer.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                November 2007
                16 October 2007
                : 107
                : 3
                : e95-e106
                aDivision of Nephrology, Department of Medicine, School of Medical Sciences, State University of Campinas, São Paulo, Brazil; bDivision of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Osaka, Japan
                109828 Nephron Exp Nephrol 2007;107:e95–e106
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 8, Tables: 1, References: 49, Pages: 1
                Original Paper


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