These studies expand the potential scope of the pathophysiologic significance of F2-isoprostanes, released during oxidant injury, to include alteration of endothelial cell biology.
The human 15-lipoxygenase (15-LO) gene was transfected into rat kidneys in vivo via intra-renal arterial injection. Three days later, acute (passive) or accelerated forms of antiglomerular basement membrane antibody-mediated glomerulonephritis were induced in transfected and nontransfected or sham-transfected controls. Studies of glomerular functions (filtration and protein excretion) and ex vivo glomerular leukotriene B4 biosynthesis at 3 hr, and up to 4 days, after induction of nephritis revealed preservation or normalization of these parameters in transfected kidneys that expressed human 15-LO mRNA and mature protein, but not in contralateral control kidneys or sham-transfected animals. The results provide in vivo-derived data supporting a direct antiinflammatory role for 15-LO during immune-mediated tissue injury.
Unilateral ureteral obstruction (UUO) leads to fibrosis of the obstructed kidney. We tested the hypothesis that interstitial fibrosis in UUO results, at least in part, from enhanced expression of transforming growth factor-beta (TGF-beta) which in turn is regulated by local angiotensin II (Ang II) generation. (The generic name TGF-beta is used to discuss properties shared by all isoforms, but special reference to other isoforms is made when specifically needed.) Using Northern blot and immunohistochemical analysis, we examined the expression of TGF-beta in rat kidneys after 24 hours (aUUO) and one week (cUUO) of obstruction. Obstructed kidneys from both periods had increased interstitial and perivascular TGF-beta immunoreactivity compared to contralateral and sham kidneys, in which immunostaining was confined to the inner medulla. Relative abundance of all TGF-beta mRNA isoforms were higher in the obstructed than in contralateral and sham kidneys in both aUUO and cUUO. Expression of TGF-beta isoforms varied according to site (cortex vs. medulla), segment of the nephron, type of cells and duration of the obstruction. The increase in TGF-beta immunoreactivity and mRNA levels in aUUO and cUUO was almost totally abolished by pretreatment with losartan. We conclude that in UUO: (a) TGF-beta gene expression is increased and differentially regulated; (b) Ang II, at least partially, mediates the overexpression of TGF-beta gene; and (c) Ang II may play a central role in fibrogenesis in this and other models of tubulointerstitial disease.
Increased F(2)-isoprostane synthesis during diabetes appears to be responsible in part for the increase in renal TGF-beta, a well-known mediator of diabetic nephropathy.
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