beta(2)-Adrenoceptor activation attenuates endotoxin-induced acute renal failure.
Abnormalities in the beta(2)-adrenergic control of organ function have been implicated in the pathogenesis of several disease states, such as septic shock. The objectives of the present study were to define the contribution of beta(2)-adrenoceptors (beta(2)-AR) to normal renal physiology and to investigate whether overexpression of renal beta(2)-AR might be potentially beneficial in preventing progressive renal damage associated with endotoxemia. Adenoviral transgenes containing the human beta(2)-AR (Adeno-beta(2)-AR) were constructed and delivered into the rat kidney by means of intraparenchymal injections. Administration of 10(9) total viral particles of Adeno-beta(2)-AR induced an approximately threefold increase in beta(2)-AR density in the renal tissue, which 2 wk after delivery, enhanced GFR and sodium reabsorption compared with control rats. The enhanced GFR was abolished by the addition of the beta(2)-AR antagonist, ICI 118,551. Administration of lipopolysaccharide (LPS) caused a reduction in GFR, beta(2)-AR density, and cAMP together with enhanced TNF-alpha mRNA in the kidney. In rats overexpressing beta(2)-AR, the reduction in baseline GFR and elevation of TNF-alpha mRNA and leukocyte infiltration into the kidney associated with the endotoxin were blocked. These findings suggested the possibility that a renal-specific overexpression of beta(2)-AR preserves basal renal function in response to a ligand-independent beta(2)-AR activation and that the delivery of Adeno-beta(2)-AR gene is a potential novel therapeutic strategy for treatment of acute renal failure associated with sepsis.
Nakamura
Akio
A
Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan. akio@med.teikyo-u.ac.jp
Imaizumi
Akira
A
Yanagawa
Yukishige
Y
Kohsaka
Takao
T
Johns
Edward J
EJ
D058186:Acute Kidney Injury / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004731:Endotoxins; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000737:chemistry / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology* / Q000627:therapeutic use*; D018805:Sepsis / Q000150:complications*; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D004731:Endotoxins; D018343:Receptors, Adrenergic, beta-2; D001616:beta-Galactosidase