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Tumor necrosis factor contributes to...

DiPetrillo, Keith Jason.

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Tumor necrosis factor contributes to early diabetic nephropathy.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Tumor necrosis factor contributes to early diabetic nephropathy./
作者:	DiPetrillo, Keith Jason.
面頁冊數:	140 p.
附註:	Chair: Frank A. Gesel.
Contained By:	Dissertation Abstracts International63-07B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3059806
ISBN:	0493755268

Tumor necrosis factor contributes to early diabetic nephropathy.
DiPetrillo, Keith Jason.

Tumor necrosis factor contributes to early diabetic nephropathy. - 140 p.

Chair: Frank A. Gesel.

Thesis (Ph.D.)--Dartmouth College, 2002.

Early renal changes during diabetes include sodium (Na) retention and renal hypertrophy. Tumor Necrosis Factor (TNF) is elevated during diabetes and is implicated in the pathogenesis of diabetic nephropathy. We tested the hypothesis that TNF contributes to Na retention and renal hypertrophy during diabetes. TNF mRNA and protein expression were enhanced in proximal tubule (PT) cells from diabetic rats. Increased TNF production and secretion from PT cells provides a source of renal TNF during diabetes. Diabetic rats exhibited increased urinary TNF excretion, Na retention, and renal hypertrophy through the first 20 days of diabetes. Administration of a soluble TNF antagonist (TNFR:Fc) to diabetic rats reduced urinary TNF excretion and prevented both Na retention and renal hypertrophy. TNF acutely stimulated Na uptake in distal tubule (DT) cells isolated from diabetic rats, but did not affect Na transport in cells from control rats, suggesting that DT cells were sensitized to acute effects of TNF during diabetes. <italic>In vitro</italic>, chronic TNF exposure sensitized DT cells to the acute effects of TNF in a time and dose-dependent manner. Similarly, TNF inhibition <italic>in vivo</italic> during diabetes abolished DT sensitization. Acutely, TNF stimulated Na uptake via amiloride-sensitive epithelial Na channels (ENaC) through the sphingomyelinase pathway and subsequent MAPK activation. The addition of exogenous ceramide reconstituted the stimulation of Na entry. Thus, TNF regulates DT Na transport through sequential chronic and acute effects. Chronic TNF exposure leads to DT sensitization that permits acute TNF-induced activation of MAPK and ENaC. TNF induced changes in DT cells underlie whole animal Na retention. We conclude that urinary TNF contributes to early diabetic nephropathy and may serve as a valuable diagnostic marker. Furthermore, inhibition of TNF during diabetes may attenuate early pathological changes in diabetic nephropathy.

ISBN: 0493755268Subjects--Topical Terms:

1017719
Biology, Molecular.

Tumor necrosis factor contributes to early diabetic nephropathy.
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500 $a Chair: Frank A. Gesel.
500 $a Source: Dissertation Abstracts International, Volume: 63-07, Section: B, page: 3245.
502 $a Thesis (Ph.D.)--Dartmouth College, 2002.
520 $a Early renal changes during diabetes include sodium (Na) retention and renal hypertrophy. Tumor Necrosis Factor (TNF) is elevated during diabetes and is implicated in the pathogenesis of diabetic nephropathy. We tested the hypothesis that TNF contributes to Na retention and renal hypertrophy during diabetes. TNF mRNA and protein expression were enhanced in proximal tubule (PT) cells from diabetic rats. Increased TNF production and secretion from PT cells provides a source of renal TNF during diabetes. Diabetic rats exhibited increased urinary TNF excretion, Na retention, and renal hypertrophy through the first 20 days of diabetes. Administration of a soluble TNF antagonist (TNFR:Fc) to diabetic rats reduced urinary TNF excretion and prevented both Na retention and renal hypertrophy. TNF acutely stimulated Na uptake in distal tubule (DT) cells isolated from diabetic rats, but did not affect Na transport in cells from control rats, suggesting that DT cells were sensitized to acute effects of TNF during diabetes. <italic>In vitro</italic>, chronic TNF exposure sensitized DT cells to the acute effects of TNF in a time and dose-dependent manner. Similarly, TNF inhibition <italic>in vivo</italic> during diabetes abolished DT sensitization. Acutely, TNF stimulated Na uptake via amiloride-sensitive epithelial Na channels (ENaC) through the sphingomyelinase pathway and subsequent MAPK activation. The addition of exogenous ceramide reconstituted the stimulation of Na entry. Thus, TNF regulates DT Na transport through sequential chronic and acute effects. Chronic TNF exposure leads to DT sensitization that permits acute TNF-induced activation of MAPK and ENaC. TNF induced changes in DT cells underlie whole animal Na retention. We conclude that urinary TNF contributes to early diabetic nephropathy and may serve as a valuable diagnostic marker. Furthermore, inhibition of TNF during diabetes may attenuate early pathological changes in diabetic nephropathy.
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